Asymmetric three- and [2 + 1]-component conjugate addition reactions for the stereoselective synthesis of polysubstituted piperidinones

Article abstract of DOI:10.1039/b701226h

The efficiency and stereoselectivity of the conjugate addition of lithium (Z)- or (E)-β-amino ester enolates, generated by lithium amide conjugate addition to an α,β-unsaturated ester or deprotonation of a β-amino ester, respectively, to a range of α,β-unsaturated acceptors has been investigated. Deprotonation of a β-amino ester with LDA, followed by conjugate addition to a chiral α,β-unsaturated oxazolidinone gives high 2,3-anti selectivity (～90% d.e.), with hydrogenolysis and purification to homogeneity generating stereodefined trisubstituted piperidinones as single stereoisomers. Asymmetric three-component couplings of α,β-unsaturated esters and alkylidene malonates initiated by lithium amide conjugate addition proceeds with high levels of 2,3-anti stereoselectivity, with hydrogenolysis giving tetrasubstituted piperidinones. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b701226h

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Asymmetric three- and [2 + 1]-component conjugate addition reactions for the
stereoselective synthesis of polysubstituted piperidinones†
Stephen G. Davies,* Paul M. Roberts and Andrew D. Smith
Received 26th January 2007, Accepted 27th February 2007
First published as an Advance Article on the web 23rd March 2007
DOI: 10.1039/b701226h
The efficiency and stereoselectivity of the conjugate addition of lithium (Z)- or (E)-b-amino ester
enolates, generated by lithium amide conjugate addition to an a,b-unsaturated ester or deprotonation
of a b-amino ester, respectively, to a range of a,b-unsaturated acceptors has been investigated.
Deprotonation of a b-amino ester with LDA, followed by conjugate addition to a chiral
a,b-unsaturated oxazolidinone gives high 2,3-anti selectivity (∼90% d.e.), with hydrogenolysis and
purification to homogeneity generating stereodefined trisubstituted piperidinones as single
stereoisomers. Asymmetric three-component couplings of a,b-unsaturated esters and alkylidene
malonates initiated by lithium amide conjugate addition proceeds with high levels of 2,3-anti
stereoselectivity, with hydrogenolysis giving tetrasubstituted piperidinones.
ammonia equivalents,2,3 with conjugate addition, followed by
enolate functionalisation4,5 giving rise to a range of enantiomeri-
Introduction
cally pure b-amino acid derivatives.6 In these conjugate addition
reactions, only the discrete monomeric b-amino ester products
are normally observed, with no observable oligomerisation of
the a,b-unsaturated ester, consistent with the rate of lithium
amide conjugate addition to the a,b-unsaturated ester being
considerably greater than the rate of b-amino enolate conju-
gate addition. Although conjugate addition and intramolecular
cyclisation reactions occur upon addition of lithium amides to
dienedioates,7–9 we have recently reported that addition of tert-
butyl 2,5-dihydrofuran-3-carboxylate 6 to lithium dibenzylamide
(1.6 eq.) gave a complex mixture of four products 7–10, comprising
the C(3)-epimeric b-amino esters 7 and 8, and the oligomeric b-
amino esters 9 and 10, which presumably derive from conjugate
addition of the in situ generated (Z)-b-amino lithium enolate to 6
(Scheme 1).10
The piperidine ring is a common feature of numerous alkaloid
natural products with immense structural diversity, ranging from
simple 2-substituted derivatives such as (S)-coniine 1 and (S)-
anabasine 2 to complex polycyclic products such as morphine 3
(Fig. 1). Although less prominent in nature, the related piperidi-
none structural family, as represented by adalinine 4 and adaline
5, have received increasing interest, as these versatile scaffolds
readily serve as advanced intermediates for piperidine synthesis.
Numerous methodologies have been developed for the synthesis
of these related structural classes in enantiomerically pure form,
and this area of research has been extensively reviewed.1
Fig. 1 Natural products containing the piperidine and piperidinone
skeletons.
Previous investigations from this laboratory have shown
that a variety of N-alkyl lithium amides derived from a-
methylbenzylamine may be considered as efficient homochiral
Scheme 1 Reagents and conditions: (i) lithium dibenzylamide, THF,
−78 ◦C.
In order to probe the possible synthetic applications of this
oligomerisation protocol, an investigation concerned with the
ability of lithium amides to promote the bespoke stereoselec-
tive oligomerisation of a,b-unsaturated acceptors was instigated.
While it was expected that regiocontrol in such anionic processes
Department of Organic Chemistry, Chemistry Research Laboratory, Uni-
versity of Oxford, Mansfield Road, Oxford, OX1 3TA, UK. E-mail: steve.
davies@chem.ox.ac.uk
† Electronic supplementary information (ESI) available: Experimental
data. See DOI: 10.1039/b701226h
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may be complicated by competing 1,2-addition,11 the ability to
promote stereoselective and discrete oligomerisation rather than
initiate uncontrolled polymerisation was envisaged to be the main
synthetic hurdle within this reaction manifold. In the literature,
several groups have reported controlled anionic dimerisation pro-
cedures of a,b-unsaturated acceptors.12 For example, Mioskowski
et al. have noted the formation of discrete oligomeric products
upon conjugate addition to nitroalkenes,13 while Takahashi et al.
have utilised multiple conjugate addition reactions as an ap-
proach to steroidal building blocks.14 Similarly, Ley et al. have
demonstrated that the lithium anion of a glycolic acid derivative
allows the asymmetric coupling of a,b-unsaturated lactones and
nitroalkenes,15 and Hanessian et al. have shown that chiral phos-
phonamides can be used for consecutive asymmetric conjugate
additions.16 It was envisaged that addition of an a,b-unsaturated
acceptor to lithium (Z)- or (E)-b-amino enolates, generated either
from lithium amide conjugate addition to an a,b-unsaturated
acceptor or deprotonation of a b-amino ester, respectively, would
selectively promote the oligomerisation process via three- and [2 +
1]-component couplings. N-Benzyl deprotection and intramolec-
ular cyclisation of the resulting b-amino acid derivatives would
give rise to polysubstituted, stereodefined piperidinones (Fig. 2).
We report herein our full investigations within this area, part of
which has been communicated previously.17
diversity. Deprotonation of (3R,aS)-11 with LDA (1.1 eq.) gave
lithium (E)-b-amino enolate 12, with subsequent addition of tert-
butyl acrylate resulting in polymerisation of the activated olefin.
Similarly, addition of tert-butyl methylene malonate to lithium
(E)-b-amino enolate 12 gave a complex mixture of oligomeric
products. Although addition of tert-butyl cinnamate to b-amino
enolate 12 returned only starting material, addition of methyl
cinnamate to b-amino enolate 12 and warming to 0 ◦C gave, at
approximately 60% conversion, a complex crude product mixture
that upon purification gave the desired product (2S,3S,1ꢀR,aS)-13
in 66% d.e.19 and 30% yield, and the b-keto ester (2S,3S,1ꢀR,aS)-
1420 in 15% yield (Scheme 2).21
Scheme 2 Reagents and conditions: (i) 11 (1.0 eq.), LDA (1.1 eq.), THF,
−78 ◦C to 0 ◦C; (ii) methyl cinnamate, THF, −78 ◦C to 0 ◦C.
Recrystallisation of 13 to homogeneity and subsequent single-
crystal X-ray analysis established the relative configuration within
13, with the absolute (2S,3S,1ꢀR,aS) configuration established
relative to the known (S)-a-methylbenzyl fragment, allowing
unambiguous assignment of the preferential C(2)–C(3) anti-
selectivity for the conjugate addition process (Fig. 3).
Fig. 2 Proposed three- and [2 + 1]-component conjugate addition
reactions for the synthesis of piperidinones.
Results and discussion
Stepwise [2 + 1]-component coupling reactions of lithium b-amino
enolates with a,b-unsaturated esters and oxazolidinones
Initial investigations concentrated upon a stepwise [2 + 1]-
component coupling procedure involving generation of the lithium
(E)-enolate 1218 of the known b-amino ester (3R,aS)-11 and
subsequent reaction with an a,b-unsaturated acceptor. It was
envisaged that screening of the susceptibility of a range of a,b-
unsaturated esters acceptors in this reaction manifold would
enable their reactivity to be quantified and facilitate high reaction
Fig. 3 Chem 3D representation of the X-ray crystal structure of
(2S,3S,1ꢀR,aS)-13 (some H atoms removed for clarity).
In order to promote further the desired conjugate addition
manifold, it was reasoned that the formation of a stable enolate
could drive the reaction, preventing any possible polymerisation
or retro-conjugate addition. N-Cinnamoyl oxazolidinones were
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considered to fulfil these properties, as conjugate addition of the
b-amino enolate 12 to such an oxazolidinone derivative would
generate a stable chelated enolate, while the steric encumberance of
the oxazolidinone would disfavour any competitive 1,2-addition.
Indeed, addition of N-cinnamoyl-4,4-dimethyl-oxazolidin-2-one
to lithium (E)-b-amino enolate 12 gave an inseparable 89 :
11 mixture of diastereoisomers 15, isolated in 49% yield and
78% d.e. after purification.22 Encouraged by this result, it was
proposed that higher levels of stereoselectivity in this protocol
could be achieved by employing double asymmetric induction.23
In the matched case, addition of homochiral (S)-N-cinnamoyl-4-
benzyl-oxazolidin-2-one 16 to lithium (E)-b-amino enolate 12 gave
(2S,3S,1ꢀR,4ꢀꢀS,aS)-17 in 86% d.e. and 62% yield, while addition
of oxazolidinone (S)-16 to the enantiomeric lithium (E)-b-amino
enolate 12 derived from (3S,aR)-11 proceeded to give 18 in only
low conversion (∼30%) and 60% d.e.24 Further optimisation of the
matched combination [lithium (E)-b-amino enolate 12 and (S)-
16] by changing the reaction stoichiometry gave improved yields
of the desired product 17: addition of 1.6 eq. of lithium (E)-b-
amino enolate 12 to N-cinnamoyl oxazolidinone 16 gave 17 with
identical stereoselectivity (86% d.e.), but in an improved 83% yield
(Scheme 3).
Benzyl-N-(p-methoxycinnamoyl)oxazolidinone 19, (S)-4-phenyl-
N-cinnamoyloxazolidinone 20 and (S)-4-phenyl-5,5-dimethyl-
N-cinnamoyloxazolidinone 21 were used as the chiral a,b-
unsaturated acceptor components, furnishing the desired products
(2S,3S,1ꢀR,4ꢀꢀS,aS)-22–24 in 88, 92 and 90% d.e. and in 57,
52 and 56% isolated yields respectively. It is noteworthy that
the 4-benzyl- and 4-phenyloxazolidinones offer similar levels of
stereocontrol in this reaction manifold, in marked contrast to
the vastly different levels of diastereoselectivity observed upon
addition of organocuprates to similar systems.25 An improved yield
of oxazolidinone derivative 24 could be achieved using 1.6 eq. of
lithium (E)-b-amino enolate 12 in the addition to oxazolidinone
19, giving 24 in 75% isolated yield (Scheme 4).
Scheme 4 Reagents and conditions: (i) 11 (1.0 eq.), LDA (1.1 eq.), THF,
−78 ◦C to 0 ◦C; (ii) (S)-N-p-methoxycinnamoyl-4-benzyloxazolidinone
19 (1.0 eq.) or (S)-N-cinnamoyl-4-phenyloxazolidinone 20 (1.0 eq.) or
(S)-4-phenyl-5,5-dimethyl-N-cinnamoyloxazolidinone 21 (1.0 eq.), THF,
−78 ◦C to 0 ◦C; (iii) 11 (1.6 eq.), LDA (1.7 eq.), THF, −78 ◦C to 0 ◦C.
The absolute configurations within 17 and 24 were proven
by chemical correlation. Treatment of SuperQuat oxazolidinone
derivative 24 with LiOMe in MeOH gave diester 13 in 97%
yield by regioselective exocyclic cleavage26 of the oxazolidinone
auxiliary, while under the same reaction conditions oxazolidinone
17 gave a 66 : 34 ratio of (2S,3S,1ꢀR,4ꢀꢀS,aS)-25 and 13, the
products of endocyclic and exocyclic oxazolidinone cleavage, in
56 and 29% yields respectively. Furthermore, hydrogenolysis of b-
amino esters 13, 17 and 24 and concomitant cyclisation furnished
(4S,5S,6R)-piperidinone 26, in 80, 76 and 84% yields as a single
diastereoisomer in each case after purification (Scheme 5).
Scheme 3 Reagents and conditions: (i) 11 (1.0 eq.), LDA (1.1 eq.), THF,
−78 ◦C to 0 ◦C; (ii) N-cinnamoyl-4,4-dimethyl-oxazolidin-2-one (1.0 eq.),
THF, −78 ◦C to rt; (iii) (S)-N-cinnamoyl-4-benzyl-oxazolidin-2-one 16
(1.0 eq.), THF, −78 ◦C to 0 ◦C; (iv) 11 (1.6 eq.), LDA (1.7 eq.), THF,
−78 ◦C to 0 ◦C.
The relative configuration within piperidinone 26 was assigned
1
using NMR spectroscopic analysis. H coupling constants were
used to indicate the axial and equatorial relationships between
the ring protons, and the 1,3-diaxial relationship between C(4)-
H and C(6)-H was confirmed through NOE difference analysis.
The absolute (4S,5S,6R) configuration of 26 was established
on the assumption that the configuration at C(6) derived from
Further application of the ‘matched’ combination of this double
asymmetric induction protocol was next investigated. (S)-4-
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oxazolidinones,27 and with matched and mismatched combina-
tions already observed upon (E)-b-amino enolate additions to
these acceptors, it was predicted that double diastereoselectivity
and crossed conjugate addition products may complicate this
reaction manifold. Addition of tert-butyl cinnamate to lithium
(R)-N-benzyl-N-a-methylbenzylamide and subsequent addition
of oxazolidinone (S)-16 gave a 25 : 15 : 60 mixture of components
that were identified as b-amino ester 11, b-amino oxazolidinone 27
(66% d.e.) and the desired product 28 (85% d.e.). Chromatographic
purification yielded the desired oxazolidinone derivative 28 in 38%
yield and 85% d.e. Subsequent hydrogenolysis of 28 (85% d.e.)
gave (4R,5S,6R)-piperidinone 29 in 68% yield and >95% d.e. after
chromatographic purification. Addition of tert-butyl cinnamate
to lithium (S)-N-benzyl-N-a-methylbenzylamide and subsequent
addition of oxazolidinone (S)-16 gave a 45 : 20 : 35 mixture of
components that were identified as b-amino ester 11, b-amino ox-
azolidinone 30 (>98% d.e.) and oxazolidinone derivative 31 (50%
d.e.). Chromatographic purification gave b-amino ester 11 as the
major reaction product in 35% yield and the desired oxazolidinone
derivative 31 (28% isolated yield, 50% d.e.). Further exhaustive
purification yielded a diastereomerically enriched sample of the
major diastereoisomer of oxazolidinone derivative 31 (90% d.e.),
which upon hydrogenolysis gave piperidinone (4S,5R,6S)-29 as the
major reaction product. Hydrogenolytic deprotection in both reac-
tion manifolds to give the enantiomeric piperidinones (4R,5S,6R)-
29 and (4S,5R,6S)-29 (indicates preferential syn-selectivity for the
tandem conjugate addition protocol, while the complex product
distributions from these reactions demonstrate that for an efficient
‘one-pot’ procedure, any possible crossed conjugate addition
products must be minimised (Scheme 6).
Scheme 5 Reagents and conditions: (i) Pd(OH)2/C, MeOH, H2 (5 atm);
(ii) LiOMe, MeOH.
lithium amide conjugate addition was (R), by analogy with
previous models developed to explain the consistently high
stereoselectivity observed during addition of lithium N-benzyl-
N-a-methylbenzylamide to a,b-unsaturated esters. The absolute
configurations within 17 and 22–24 were assigned by analogy
(Fig. 4).
The use of alkylidene malonates as suitable acceptors in this
tandem reaction manifold was next investigated. Although lithium
(S)-N-benzyl-N-a-methylbenzylamide adds in a conjugate fashion
to a,b-unsaturated esters with high diastereoselectivity, its reaction
with alkylidenemalonates has not previously been explored. Initial
studies therefore focused upon treatment of model alkyliden-
emalonates with lithium (S)-N-benzyl-N-a-methylbenzylamide.
Addition of diethyl benzylidenemalonate to lithium (S)-N-benzyl-
N-a-methylbenzylamide returned only starting material, although
addition of diethyl phenylallylidenemalonate gave a low yield of
the reduced product 32.28,29 In both cases no trace of any conjugate
addition products were noted (Scheme 7).
It was proposed that the inability of lithium (S)-N-benzyl-N-a-
methylbenzylamide to act as a nucleophile in conjugate additions
to alkylidenemalonates could be used to advantage, minimising
competing cross-conjugate addition in a one-pot reaction mani-
fold. Furthermore these acceptors would also promote the efficient
capping of the oligomerisation reaction, as conjugate addition
of a b-amino enolate to an alkylidenemalonate would generate
a stabilised malonate enolate. Addition of tert-butyl cinnamate
(1 eq.) to lithium (S)-N-benzyl-N-a-methylbenzylamide (2 eq.)
generated the lithium (Z)-b-amino enolate 33, with subsequent
addition of a THF solution of diethyl benzylidenemalonate (2 eq.)
giving (2S,3R,1ꢀR,aS)-34 in 90% d.e. (the ratio of 34 to the
one minor diastereoisomer in the crude product was 95 : 5).
Chromatographic purification gave 34 in 81% yield and in >95%
d.e., with hydrogenolysis giving tetrasubstituted piperidinone
(3S,4R,5S,6R)-35 in 81% yield and as a single diastereoisomer
(>98% d.e.) after purification. The relative configuration within
Fig. 4 3J coupling constants and NOE data for piperidinone 26.
Having probed the susceptibility of a range of a,b-unsaturated
esters and oxazolidinones toward the conjugate addition of a b-
amino ester enolate, extension to a ‘one-pot’ three-component
coupling protocol was investigated.
Three-component coupling reactions
As the [2 + 1] conjugate addition protocol proceeded efficiently
with chiral N-cinnamoyl oxazolidinones as the a,b-unsaturated
acceptor component, the development of a tandem oligomeri-
sation protocol concentrated upon their use in a tandem, ‘one-
pot’ strategy. As previous investigations from this laboratory
have shown that double diastereoselectivity is observed upon
conjugate addition of chiral lithium amides to chiral N-cinnamoyl
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Scheme
6
Reagents and conditions: (i) lithium (R)-N-benzyl-N-a-methylbenzylamide (1.1 eq.), THF, −78 ◦C; (ii) lithium (S)-N-benzyl-
N-a-methylbenzylamide (1.1 eq.), THF, −78 ◦C; (iii) (S)-N-cinnamoyl-4-benzyl-oxazolidin-2-one 16 (1.0 eq.), THF, −78 ◦C to 0 ◦C; (iv) Pd(OH)2/C,
MeOH, H2 (5 atm).
Scheme
7
Reagents and conditions: (i) lithium (S)-N-benzyl-
N-a-methylbenzylamide (1.6 eq.), THF, −78 ◦C.
piperidinone 35 was assigned using NMR spectroscopic analysis,
relative to the known configuration at C(6) arising from lithium
amide conjugate addition (Scheme 8).
In an attempt to identify the configuration within the minor
product diastereoisomer in this protocol, a stepwise [2 + 1]-
component coupling procedure was investigated. Treatment of
b-amino ester (3R,aS)-11 with LDA gave the corresponding
lithium (E)-b-amino enolate-12, and subsequent addition of
diethyl benzylidenemalonate gave (2S,3S,1ꢀR,aS)-36 in 90% d.e.
(crude product ratio 36:34 95 : 5). Although this unoptimised
procedure proceeded to only 40% conversion, 36 was isolated by
chromatography in 33% yield and >95% d.e. after purification.
Comparison of the 1H NMR spectrum of 36 and that of the crude
product mixture from the three-component coupling protocol
indicated no trace of 36 in the tandem reaction, indicating that the
minor diastereoisomer in the tandem coupling reaction manifold
arises from incomplete stereocontrol at C(2) upon alkylation of
Scheme
8
Reagents and conditions: (i) lithium (S)-N-benzyl-N-a-
methylbenzylamide (2.0 eq.), THF, −78 ◦C; (ii) diethyl benzylidene-
malonate (1.0 eq.), THF, −78 ◦C to 0 ◦C; (iii) Pd(OH)2/C, MeOH, H2
(5 atm).
b-amino enolate 33. Treatment of 36 with Pearlman’s catalyst and
H2 (5 atm) promoted hydrogenolysis and concomitant cyclisation,
giving piperidinone (3R,4S,5S,6R)-37 in 91% yield and as a single
diastereoisomer (>98% d.e.) after chromatography. The relative
configuration within 37 was elucidated by 1H NMR spectroscopy
and NOE difference experiments (Scheme 9).
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anti-stereochemical induction observed in this tandem reaction
protocol was confirmed by single crystal X-ray analysis of 42,30
with the absolute configurations of the major diastereoisomers
38–41 and 43 assigned by direct analogy.
With a range of b-amino esters prepared utilising this three-
component coupling procedure, their conversion to piperidinones
was investigated. Hydrogenolysis of b-amino esters 38 and 40–
42 gave the tetrasubstituted piperidinones 44–47 in high yields
(>75%) and as single diastereoisomers in each case after chro-
matography. The relative configuration within piperidinones 44–
47 was confirmed by 1H NMR spectroscopy and NOE difference
experiments, with the absolute configuration derived from the pre-
dictable C(6) configuration arising from lithium amide conjugate
addition (Table 2).
Table 2 Synthesis of compounds 35 and 44–47.
Scheme 9 Reagents and conditions: (i) 11 (1.0 eq.), LDA (1.1 eq.), THF,
−78 ◦C to 0 ◦C; (ii) diethyl benzylidenemalonate (1.0 eq.), THF, −78 ◦
C
to 0 ◦C; (iii) Pd(OH)2/C, MeOH, H2 (5 atm).
The generality of this one-pot three-component coupling re-
action protocol was then examined further. Variation of the a,b-
unsaturated ester component (cinnamic and crotonic esters) and
incorporation of a range of aryl-, alkenyl- and alkyl-substituted
malonates was investigated (Table 1). Analysis of the product
distributions from these reactions show that higher yields and
diastereoselectivities are observed with b-aryl substituents in both
ester and malonate components (d.r. typically >95 : <5), although
the reaction successfully tolerates both b-alkyl and b-alkenyl
functionality (d.r. 94 : 6 to 89 : 11). The desired b-amino esters
38–40 generated in this fashion could be purified to homogeneity
in good yield by chromatographic purification, although 42 and 43
required further purification by recrystallisation. The C(2)–C(3)
Substrate R1
R2
R3
R4
Et
Me 44
Me 45
Product Yield (%)
34
38
40
41
42
Ph
Ph
Ph
Ph
tBu
tBu
tBu
tBu
Ph
Ph
35
81
91
78
80
75
Me
PhCH2CH2
PhCH2CH2
Et
Et
46
47
Me iPr
Table 1 Synthesis of compounds 34 and 38–43.
R1
R2
R3
R4
Crude d.r.a
Product
Yield (%)
Ph
Ph
tBu
tBu
tBu
tBu
tBu
iPr
Ph
4-BrC6H4
4-BrC6H4
Me
Et
Et
Et
Et
>95 : <5
>95 : <5
>95 : <5
94 : 6
91 : 9
92 : 8
34
38
39
40
41
42
43
81b
Me
Me
Me
Et
Et
Et
63b
3,4-(MeO)2C6H3
Ph
Ph
Me
Me
70b
67b
64c
63c (46)d
52c (37)d
iPr
89 : 11
a As determined by 400 MHz 1H spectroscopic analysis of the crude reaction mixture. b Isolated yield of single diastereoisomer. c Isolated yield of
inseparable diastereoisomeric mixture. d Isolated yield of a single diastereomer after recrystallisation.
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enolate addition to the chiral N-cinnamoyl-oxazolidinones is
consistent with transition state 50 or 51, in which the syn-s-trans
or anti-s-cis conformation is adopted (Fig. 5). A similar transition
state has been used to account for the diastereoselectivity observed
upon addition of tert-butyl ester enolates to a,b-unsaturated esters
by Yamaguchi et al.34
These constraints can also be used to account for the pref-
erential 2,3-syn selectivity of the lithium (E)-enolate and 2,3-
anti-selectivity of the lithium (Z)-enolates upon addition to the
malonate-derived acceptors. In these cases, allowing the smallest
C(3)-H substituent of the electrophile rather then the C(3)-alkyl
group to occupy the sector occupied by the C(3)-alkyl substituent
of the b-amino enolate predicts the correct 2,3-syn or 2,3-anti
configuration respectively (Fig. 6).
Stereochemical outcome of ester enolate conjugate
additions
Many explanations for the observed stereoselectivity of in-
termolecular enolate conjugate addition reactions have been
proposed.31 In the above reaction manifolds, the 2,3-anti or 2,3-syn
stereoselectivity observed within these conjugate addition reac-
tions alternates with a change in enolate geometry and variation in
the a,b-unsaturated ester component from an ester/oxazolidinone
to a malonate derivative. On the assumption that the reacting b-
amino enolate is monomeric in solution32 and that the favourable
transition state for conjugate addition of the (E)- or (Z)-b-amino
enolate to the a,b-unsaturated acceptor has substituents on the
two prostereogenic centres staggered to minimise unfavourable
non-bonding interactions,31b speculative models consistent with
the stereochemical outcome of these reactions may be presented.
The selectivity observed at C(2) upon conjugate addition in each
case can be accounted for using the concept of allylic strain,33 with
either the lithium (E)-enolate 12 formed from deprotonation of b-
amino ester 11 with LDA or the lithium (Z)-enolate 33 formed by
conjugate addition predicted to adopt a reactive conformation in
=
which the C(3)-H bond is eclipsed with the C C bond of the
enolate, with preferential alkylation anti to the N-benzyl-N-a-
methylbenzyl group. The variation in configuration at C(3) in these
conjugate addition reactions is striking and must be due in part to
the nature of the a,b-unsaturated acceptor in each case. The a,b-
unsaturated acceptors may undergo conjugate addition through
either the s-cis or s-trans conformation, although attempts to
delineate their preferred conformation in these reaction manifolds
by enolate trapping proved inconclusive. However, assuming that
chelation control between the lithium b-amino enolate and the a,b-
=
unsaturated acceptor is operating in each case, the C C of the a,b-
unsaturated acceptor is restricted to occupy a synclinal/gauche
Fig. 6 Rationale for the stereochemical outcome of the stepwise and
tandem conjugate addition reactions to alkylidene malonates.
=
orientation to the C C of the enolate. Quantitatively, the correct
configuration at C(3) can be predicted by allowing preferential
=
orientation of the C C of the a,b-unsaturated acceptor syn to the
quadrant occupied by the C–OLi bond and anti to that of the C–
OR bond. For example, using these constraints, the stepwise [2 +
1] reactions of the lithium (E)-enolate with methyl (E)-cinnamate
permits reaction via either transition state 48 or 49, which allow
the cinnamate to react via either the s-cis or s-trans conformation.
Similarly, the high matched diastereoselectivity observed upon
Conclusion
In conclusion, the deprotonation of a b-amino ester, followed
by conjugate addition to a chiral a,b-unsaturated oxazolidinone
gives high 2,3-syn selectivity (∼90% d.e.), with hydrogenolysis and
purification to homogeneity generating stereodefined, trisubsti-
tuted piperidinones as single diastereoisomers. Asymmetric three-
component couplings of a,b-unsaturated esters and alkylidene
malonates initiated by lithium amide conjugate addition proceed
with high levels of 2,3-anti stereoselectivity, with hydrogenolysis
giving tetrasubstituted piperidinones. The utility of this method-
ology for a variety of applications including total synthesis is
currently under investigation in our laboratory.
Experimental
General
All reactions involving organometallic or other moisture-sensitive
reagents were performed under an atmosphere of nitrogen using
standard vacuum line techniques. All glassware was flame-dried
and allowed to cool under vacuum. THF was distilled under an
Fig. 5 Rationale for the stereochemical outcome of the [2 + 1] stepwise
and tandem conjugate addition reactions.
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◦
atmosphere of dry nitrogen from sodium benzophenone ketyl.
Water was distilled. n-Butyllithium was used as a solution in
hexanes at the molarity stated. All other solvents and reagents
were used as supplied (Analytical or HPLC grade), without
prior purification. Reactions were dried with MgSO4. Thin layer
chromatography (t.l.c.) was performed on aluminium sheets
coated with 60 F254 silica. Sheets were visualised using iodine,
UV light or 1% aqueous KMnO4 solution. Flash chromatography
was performed on Kieselgel 60 silica. Nuclear magnetic resonance
(NMR) spectra were recorded on a Bruker DPX 400 (1H: 400 MHz
and 13C: 100.6 MHz) spectrometer, or where stated on a Bruker
AMX 500 (1H: 500 MHz and 13C: 125.3 MHz) spectrometer in
the deuterated solvent stated. All chemical shifts (d) are quoted
in ppm and coupling constants (J) in Hz. Coupling constants are
quoted twice, each being recorded as observed in the spectrum
without averaging. Residual signals from the solvents were used
as an internal reference. 13C multiplicities were assigned using
a DEPT sequence. In all cases, the reaction diastereoselectivity
via cannula and stirred at −78 C for 2 h before the addition of
another a,b-unsaturated carbonyl component. After 10 min, the
reaction was warmed to 0 ◦C for 2 h before cooling to −78 ◦C
and the addition of saturated aqueous ammonium chloride. After
warming to rt, the resultant solution was partitioned between
brine and 1 : 1 DCM–Et2O, and the organic extracts dried,
filtered and concentrated in vacuo before purification by column
chromatography.
Representative procedure 3
Pd(OH)2/C (50% by mass) was added to a solution of the
substrate in degassed MeOH and the resultant black suspension
stirred under a hydrogen atmosphere (5 atm) for 16 h. After
depressurisation, the reaction mixture was filtered through a plug
of Celite (eluent MeOH), concentrated in vacuo and the residue
purified by column chromatography on silica gel.
1
was assessed by peak integration of the H NMR spectrum of
Preparation of 1-tert-butyl-5-methyl (2S,3S,1ꢀR,aS)-2-[1ꢀ-phenyl-
1ꢀ-(N-benzyl-N-a-methylbenzylamino)methyl]-3-phenyl-
pentanedioate 13 and 1,7-di-tert-butyl (2S,3S,1ꢀR,aS)-2-
[1ꢀ-phenyl-1ꢀ-(N-benzyl-N-a-methylbenzylamino)methyl]-3-
phenyl-5-oxoheptanedioate 14
the crude reaction mixture. Infrared spectra were recorded on
a Perkin–Elmer 1750 IR Fourier Transform spectrophotometer
using either thin films on NaCl plates (film) or KBr discs (KBr) as
stated. Only the characteristic peaks are quoted. Low resolution
mass spectra (m/z) were recorded on VG MassLab 20–250 or
Micromass Platform 1 spectrometers and high resolution mass
spectra (HRMS) on a Micromass Autospec 500 OAT spectrometer
or on a Waters 2790 Micromass LCT Exact Mass Electrospray
Ionisation mass spectrometer. Techniques used were chemical
ionisation (CI, NH3), atmospheric pressure chemical ionisation
(APCI) or electrospray ionisation (ESI) using partial purification
by HPLC with methanol–acetonitrile–water (40 : 40 : 20) as
eluent. Optical rotations were recorded on a Perkin–Elmer 241
polarimeter with a water-jacketed 10 cm cell and are given
in units of 10−1 deg cm2 g−1. Concentrations are quoted in g
per 100 ml. Melting points were recorded on a Leica VMTG
Galen III apparatus and are uncorrected. Elemental analyses were
performed by the microanalysis service of the Inorganic Chemistry
Laboratory, Oxford.
Following Representative procedure 1, LDA (2.0 M, 2.64 mmol,
1.32 ml), 11 (2.4 mmol, 1.0 g) in THF (5 ml) and methyl cinnamate
(2.4 mmol, 390 mg) gave, after column chromatography on silica
gel (hexane–Et2O 15 : 1 to 10 : 1), 13 (408 mg, 30%) as a mixture of
diastereoisomers (66% d.e.). Recrystallisation (hexane–Et2O) gave
13 as white blocks and as a single diastereoisomer, [a]2D4 +30.4 (c
1.0, CHCl3); C38H43NO4 requires C 79.0; H 7.5; N, 2.4%; found
C 78.7; H 7.5; N, 2.3%; vmax (KBr) 3027, 2933 (C–H), 1741, 1722
=
(C O), 1146 (C–O); dH (500 MHz, CDCl3) 1.01 (3H, d, J7.0,
C(a)Me), 1.26 (9H, s, OC(Me)3), 2.42 (1H, dd, J4A,4B16.0, J4A,33.4,
C(4)HA), 2.94 (1H, dd, J4B,4A16.0, J4B,312.0, C(4)HB), 3.09 (1H,
app dt, J3,4B12.0, J3,4A;3,23.5, C(3)H), 3.32 (3H, s, CO2Me), 3.47
ꢀ
(1H, dd, J2,1 11.9, J2,33.9, C(2)H), 3.58 (1H, AB, J14.2, NCHA),
4.05 (1H, AB, J14.2, NCHB), 4.21 (1H, q, J7.0, C(a)H), 4.30 (1H,
d, J5,411.9, C(1ꢀ)H), 7.05–7.44 (20H, m, Ph); dC (50 MHz, CDCl3)
16.5 (C(a)Me), 28.0 (OC(Me)3), 32.4 (C(4)H2), 40.3 (C(3)H), 51.1
(NCH2), 51.3 (OMe), 54.2, 57.2, 62.8 (C(2)H, C(1ꢀ)H and C(a)H),
80.7 (OC(Me)3), 126.4, 126.5, 126.7, 127.6, 127.8, 128.2, 128.4,
Representative procedure 1
LDA (1 M, 1.1 eq.) was added dropwise to a stirred solution of the
requisite b-amino ester (1 eq.) in anhydrous THF at −78 ◦C under
nitrogen and after 10 min was allowed to warm to 0 ◦C. After
30 min, the enolate solution was recooled to −78 ◦C, prior to the
addition of a conjugate acceptor (1 eq.) in anhydrous THF via
129.0, 129.6 (Pho/m/p), 136.8, 140.2, 141.7, 144.2 (Phipso), 171.8,
172.6 (C O); m/z APCI 578.4, (MH+, 75%), 522.1 (MH+
−
+
=
C4H8, 10%). The mother liquors were further purified by column
chromatography to give the minor diastereoisomer of unknown
absolute configuration as a white foam (13 mg, 1%); vmax 3030,
2978 (C–H), 1738, 1721 (C O), 1151 (C–O); dH (300 MHz,
CDCl3) 0.84 (9H, s, OC(Me)3), 0.91 (3H, d, J7.0, C(a)Me), 2.01
(1H, dd, J4A,4B16.6, J4A,32.9, C(4)HA), 2.69 (1H, dd, J4B,4A16.6,
◦
cannula. After 15 min ◦the solution was warmed to 0 C for 2 h
=
before cooling to −78 C and the addition of saturated aqueous
ammonium chloride. After warming to rt, the resultant solution
was partitioned between brine and 1 : 1 DCM–Et2O, and the
organic extracts were dried, filtered and concentrated in vacuo
before purification by column chromatography.
ꢀ
J
4B,312.8, C(4)HB), 3.24 (1H, dd, J2,1 11.7, J2,33.0, C(2)H), 3.58
(3H, s, CO2Me), 3.78 (1H, AB, J13.5, NCHA), 4.00 (1H, d, J11.7,
C(1ꢀ)H), 4.16–4.25 (2H, m, C(a)H and C(3)H), 4.30 (1H, AB,
J13.5, NCHB), 6.99–7.71 (20H, m, Ph); dC (50 MHz, CDCl3)
14.0 (C(a)Me), 27.2 (OC(Me)3), 32.7 (C(4)H2), 38.7 (C(2)H), 50.9
(NCH2), 51.3, 55.0, 55.2, 59.7 (OMe, C(3)H, C(1ꢀ)H and C(a)H),
80.2 (OC(Me)3), 126.5, 126.9, 127.3, 127.7, 127.9, 128.2, 128.4,
Representative procedure 2
n-Butyllithium (1.55 eq.) was added dropwise to a stirred solution
of (S)-N-benzyl-N-a-methylbenzylamine (1.6 eq.) in anhydrous
THF at −78 ◦C and stirred for 30 min under nitrogen. A solution of
the a,b-unsaturated ester in anhydrous THF was added dropwise
128.7, 129.3, 129.8 (Pho/m/p), 139.1, 139.7, 142.7 (Phipso), 171.3,
173.1 (C O); m/z APCI 578.4, (MH+, 100%), 600.7 (MNa+,
+
=
1412 | Org. Biomol. Chem., 2007, 5, 1405–1415
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10%). Further elution gave 14 (121 mg, 15%) as a white foam,
C43H51NO5 requires C, 78.0; H, 7.8; N, 2.1%; found C, 77.7; H,
7.7; N, 2.1%; [a]2D3 +27.0 (c 1.0, CHCl3); vmax (KBr) 2978 (C–H),
(OC(Me)3), 126.5, 127.1, 127.7, 127.8, 128.3, 128.4, 128.8, 129.1,
129.4, 129.8 (Pho/m/p), 135.2, 137.4 140.5, 142.9, 144.2 (Phipso),
+
+
=
153.4, 171.7, 171.9 (C O); m/z APCI 723.7 (MH , 100%), 745.6
(MNa+, 35%); HRMS (CI+) C47H51N2O5 requires 723.3798; found
723.3794.
=
1722 (C O), 1147 (C–O); dH (500 MHz, CDCl3) 1.02 (3H, d,
J6.8, C(a)Me), 1.28 and 1.38 (2 × 9H, s, OC(Me)3), 2.57 (1H, dd,
J
4A,4B17.2, J4A,32.8, C(4)HA), 2.94 (2H, s, C(6)H2), 3.12–3.16 (1H,
Using 1.6 eq. of enolate, following representative procedure 1,
LDA (2.0 M, 1.28 mmol, 0.64 ml, 1.7 eq.), 11 (1.20 mmol, 500 mg,
1.6 eq.) in THF (5 ml) and 16 (0.75 mmol, 230 mg, 1.0 eq.) in THF
(5 ml) gave, after purification by column chromatography on silica
gel (hexane–Et2O 5 : 1), 17 as a white foam (449 mg, 83%, 86%
d.e.).
m, C(3)H), 3.23 (1H, dd, J4B,4A17.2, J4B,311.5, C(4)HB), 3.46 (1H,
ꢀ
dd, J2,1 11.8, J2,33.7, C(2)H), 3.60 (1H, AB, J14.2, NCHA), 4.08
(1H, AB, J14.2, NCHB), 4.23 (1H, q, J6.8, C(a)H), 4.28 (1H, d,
1 ,211.8, C(1ꢀ)H), 7.02–7.44 (20H, m, Ph); dC (50 MHz, CDCl3)
ꢀ
J
16.4 (C(a)Me), 27.9, 28.0 (OC(Me)3 × 2), 39.2 (C(3)H), 41.0,
50.4, 51.1 (C(4)H2, C(6)H2 and NCH2), 54.2, 57.1, 62.9 (C(2)H,
C(1ꢀ)H, C(a)H), 80.7, 81.5 (2 × OC(Me)3), 126.5, 126.6, 126.7,
127.7, 127.8, 128.2, 128.3, 128.6, 129.0, 129.7 (Pho/m/p), 136.8,
140.1, 141.7, 144.3 (Phipso), 166.1, 172.0 (2 × CO2C(Me)3), 201.2
Preparation of (4S,5S,6R)-4,6-diphenyl-5-tert-
butoxycarbonyl-piperidin-2-one 26 (from 13)
Following Representative procedure 3, Pd(OH)2/C (60 mg) and
13 (120 mg, 0.20 mmol) in MeOH (5 ml) gave, after purification by
column chromatography on silica gel (hexane–EtOAc 5 : 1), 26 as
a white solid (56 mg, 80%); [a]2D1 −17.4 (c 0.65, CHCl3); vmax (KBr)
+
+
+
=
(C(5) O); m/z APCI 662.4 (MH , 100%), 684.0 (MNa , 15%).
X-Ray crystal structure determination for 13. Data were
collected using an Enraf–Nonius DIP2000 diffractometer with
graphite-monochromated Mo-Ka radiation using standard pro-
cedures at 100 K. The structure was solved by direct methods,
full matrix and least-squares refinement with non-hydrogen atoms
in anisotropic approximation. Hydrogen atoms were placed in
calculated positions and included in the final refinement with fixed
positional and thermal parameters. A total of 388 parameters
were refined. A three-term Chebychev polynomial was used
as the weighting scheme. All crystallographic and refinement
calculations were carried out using CRYSTALS.35
=
=
3387 (N–H), 2978 (C–H), 1711 (C Oester), 1654 (C Olactam), 1167
(C–O); dH (500 MHz, C6D6) 0.85 (9H, s, OC(Me)3), 2.57 (1H, dd,
J
J
3A,3B17.3, J3A,45.5, C(3)HA), 2.88 (1H, m, C(4)H), 2.92 (1H, dd,
5,45.5, J5,65.0, C(5)H), 3.60 (1H, dd, J3B,3A17.3, J3B,413.2, C(3)HB),
4.30 (1H, d, J6,55.0, C(6)H), 6.92 (1H, br s, NH), 6.98–7.19 (10H,
m, Ph); dC (50 MHz, CDCl3) 27.4 (OC(Me)3), 32.5 (C(3)H2),
40.9 (C(5)H), 51.8 (C(4)H), 59.0 (C(6)H), 80.7 (OC(Me)3), 126.5,
127.2, 127.3, 128.2, 128.5, 128.6 (Pho/m/p), 138.3, 140.0 (Phipso),
168.7, 172.6 (C(2) and CO2C(Me)3); m/z APCI+ 352.1 (MH+,
10%), 374.1 (MNa+, 20%), 296.1 (MH+ − C4H8, 100%); HRMS
(CI+) C22H26NO3 requires 352.1920; found 352.1913.
13 (C38H43NO4): M = 577.76, orthorhombic, space group
˚
˚
˚
P212121, a = 11.2640(2) A, b = 16.6340(3) A, c = 17.0480(2) A,
3
−1
˚
V = 3194.2 A , Z = 4, l = 0.07 mm , colourless block, crystal
dimensions = 0.4 × 0.4 × 0.5 mm3. A total of 3793 unique
reflections were measured for 1.81 < 2h < 26.78◦, and 3618
reflections were used in the refinement. The final parameters were
wR2 = 0.031 and R1 = 0.025 [I > 3r(I)]. CCDC reference number
634494. For crystallographic data in CIF or other electronic
format see DOI: 10.1039/b701226h.†
Preparation of (4S,5S,6R)-4,6-diphenyl-5-(tert-
butoxycarbonyl)piperidin-2-one 26(from 17)
Following Representative procedure 3, Pd(OH)2/C (75 mg) and
17 (150 mg, 0.21 mmol) in MeOH (5 ml) gave, after purification by
column chromatography on silica gel (hexane–EtOAc 5 : 1), 25 as
a white solid (50 mg, 76%) with identical spectroscopic properties
to that above.
Preparation of tert-butyl (2S,3S,1ꢀR,4ꢀꢀS,aS)-2-(1ꢀ-phenyl-1ꢀ-N-
benzyl-N-a-methylbenzylamino)-3-phenyl-5-oxo-5-(4ꢀꢀ-
benzyloxazolidin-2ꢀꢀ-one)pentanoate 17
Preparation of 1-tert-butyl-5-ethyl (2S,3R,1ꢀR,aS)-2-
[1ꢀ-phenyl-1ꢀ-(N-benzyl-N-a-methylbenzylamino)methyl]-3-
phenyl-4-ethoxycarbonyl-pentanedioate 34
Following Representative procedure 1, LDA (2.0 M, 1.06 mmol,
0.53 ml), 11 (0.96 mmol, 400 mg) in THF (5 ml) and (S)-N-
cinnamoyl-4-benzyloxazolidin-2-one 16 (0.96 mmol, 295 mg) in
THF (5 ml) gave, after purification by column chromatography
on silica gel (hexane–Et2O 5 : 1), 17 (432 mg, 62%) as a white
foam (86% d.e.); [a]D22 +51.8 (c 1.0, CHCl3); vmax (KBr) 2977
Following Representative procedure 2, n-BuLi (2.5 M, 2.24 mmol,
0.89 ml), (S)-N-benzyl-N-a-methylbenzylamine (500 mg,
2.30 mmol) in THF (5 ml), tert-butyl cinnamate (234 mg,
1.15 mmol) in THF (3 ml) and diethyl benzylidenemalonate
(571 mg, 2.30 mmol) in THF (2 ml) gave, after purification by
column chromatography on silica gel (hexane–Et2O 6 : 1), 34 as
=
(C–H), 1782, 1718, 1702 (C O), 1147 (C–O); dH (500 MHz,
CDCl3) 1.06 (3H, d, J6.8, C(a)Me), 1.46 (9H, s, OC(Me)3),
ꢀꢀ
ꢀꢀ
2.37 (1H, dd, JA,B13.5, JA,4 9.6, C(4 )CHAPh), 2.78 (1H, dd,
a hygroscopic white foam (617 mg, 81%); vmax (film) 2978 (C–H),
ꢀꢀ
24
=
ꢀꢀ
J
B,A13.5, JB,4 3.1, C(4 )CHBPh), 2.91 (1H, dd, J4A,4B17.4, J4A,34.8,
1757, 1732 (C O), 1141 (C–O); [a]D −29.3 (c 1.0, CHCl3); dH
ꢀ
C(4)HA), 3.26–3.30 (1H, m, C(3)H), 3.52 (1H, dd, J2,1 11.8, J2,33.5,
C(2)H), 3.57 (1H, AB, J14.2, NCHA), 3.86 (1H, dd, J4B,4A17.4,
(400 MHz, CDCl3) 0.72 (3H, t, J7.1, OCH2CH3), 1.06 (3H,
d, J6.8, C(a)Me), 1.25 (3H, t, J7.1, OCH2CH3), 1.66 (9H, s,
CO2C(Me)3), 3.32 (1H, dd, J3,412.0, J3,21.0, C(3)H), 3.44 (1H, AB,
J
4B,310.6, C(4)HB), 4.02–4.10 (2H, m, C(5ꢀꢀ)H2), 4.05 (1H, AB,
ꢀ
J14.2, NCHB), 4.20 (1H, q, J6.8, C(a)H), 4.36–4.40 (1H, m,
C(4ꢀꢀ)H), 4.45 (1H, d, J11.8, C(1ꢀ)H), 6.96–7.42 (25H, m, Ph); dC
(50 MHz, CDCl3) 16.9 (C(a)Me), 28.2 (OC(Me)3), 34.7 (C(4)H2),
37.4 (C(4ꢀꢀ)CH2Ph), 40.5 (C(2)H), 51.2 (NCH2), 54.7, 54.9, 57.7,
63.6 (C(3)H, C(1ꢀ)H, C(4ꢀꢀ)H and C(a)H), 65.8 (C(5ꢀꢀ)H2), 81.1
J14.4, NCHA), 3.55 (1H, dd, J2,1 12.2, J2,31.0, C(2)H), 3.62–3.66
(3H, m, OCH2CH3 and C(4)H), 3.83 (1H, AB, J14.4, NCHB),
4.02 (1H, dq, JA,B10.7, JA,CH37.1, OCHACH3), 4.11 (1H, q, J6.8,
C(a)H), 4.17 (1H, dq, JB,A10.7, JB,CH37.1, OCHBCH3), 4.72 (1H,
d, J12.2, C(1ꢀ)H), 6.94–6.98 (2H, m, Ph), 7.14–7.37 (18H, m,
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Ph); dC (50 MHz, CDCl3) 13.4, 14.1 (OCH2CH3), 17.5 (C(a)Me),
28.3 (CO2C(Me)3), 43.6 (C(3)H), 51.3 (NCH2), 54.1, 57.0,
58.1 (C(4)H, C(2)H, and C(a)H), 60.9, 61.3 (OCH2CH3), 64.1
(C(1ꢀ)H), 81.2 (CO2C(Me)3), 126.2, 126.3, 126.7, 127.3, 127.7,
127.9, 128.3, 128.8, 129.1, 130.5 (Pho/m/p), 137.2, 140.6, 142.4,
144.7 (Phipso), 167.7, 167.9, 171.9 (CO2C(Me)3 and CO2Et × 2);
m/z APCI+ 664.7 (MH+, 100%), 608.3 (MH+ − C4H8, 10%);
HRMS (CI+) C42H50NO6 requires 664.3638; found 664.3642.
by column chromatography on silica gel (Et2O–hexane 2 : 1),
37 (52 mg, 91%) as a colourless oil; vmax (film) 3309 (N–H),
23
=
2979 (C–H), 1725, 1670 (C O), 1159 (C–O); [a]D −61.8 (c 1.0,
CHCl3); dH (400 MHz, CDCl3) 0.78 (9H, s, CO2C(Me)3), 1.09
(3H, t, J7.1, OCH2CH3), 3.47 (1H, d, J3,411.8, C(3)H), 3.54 (1H,
dd, J5,412.8, J5,65.8, C(5)H), 3.78 (1H, app t, J4,3;4,512.3, C(4)H),
4.06–4.16 (2H, m, OCH2CH3), 5.06 (1H, dd, J6,55.8, J6,NH3.6,
C(6)H), 6.50 (1H, br s, NH), 7.11–7.41 (10H, m, Ph); dC (50 MHz,
CDCl3) 13.9 (OCH2CH3), 27.0 (CO2C(Me)3), 39.3, 50.5, 56.8
and 57.5 (C(3)H, C(4)H, C(5)H and C(6)H), 61.4 (OCH2CH3),
81.7 (CO2C(Me)3), 127.3, 127.5, 128.1, 128.5, 128.6 (Pho/m/p),
Preparation of (3S,4R,5S,6R)-3-ethoxycarbonyl-4,6-diphenyl-
5-(tert-butoxycarbonyl)piperidin-2-one 35
=
138.0, 139.9 (Phipso), 167.3, 168.3, 169.2 (C(2) O, CO2C(Me)3 and
Following Representative procedure 3, Pd(OH)2/C (75 mg) and
34 (150 mg, 0.23 mmol) in MeOH (5 ml) gave, after purification
by column chromatography on silica gel (Et2O–hexane 2 : 1), 35
CO2Et); m/z APCI+ 424.2 (MH+, 35%), 446.1 (MNa+, 30%), 368.2
(MH+ − C4H8, 100%); HRMS (CI+) C25H30NO5 requires 424.2124;
found 424.2127.
(78 mg, 81%) as a colourless oil, vmax (film) 3311 (N–H), 2977 (C–
23
=
H), 1723, 1666 (C O), 1153 (C–O); [a]D −72.1 (c 1.0, CHCl3); dH
(400 MHz, CDCl3) 0.92 (9H, s, CO2C(Me)3), 1.06 (3H, t, J7.1,
OCH2CH3), 3.15 (1H, app t, J5,4;5,64.5, C(5)H), 3.93 (1H, dd,
Acknowledgements
The authors wish to thank New College, Oxford, for a Junior
Research Fellowship (A. D. S.).
J
4,312.7, J4,53.9, C(4)H), 4.03–4.13 (2H, m, OCH2CH3), 4.65 (1H,
d, J12.7, C(3)H), 5.09 (1H, d, J6,55.2, C(6)H), 6.13 (1H, br s, NH),
7.23–7.37 (10H, m, Ph); dC (50 MHz, CDCl3) 13.9 (OCH2CH3),
27.4 (CO2C(Me)3), 44.6, 49.8, 52.0 and 58.8 (C(3)H, C(4)H, C(5)H
and C(6)H), 61.3 (OCH2CH3), 81.1 (CO2C(Me)3), 126.4, 127.6,
127.7, 128.3, 128.6, 128.7 (Pho/m/p), 137.8, 138.1 (Phipso), 168.8,
References and notes
1 For example, see: M. G. P. Buffat, Tetrahedron, 2004, 60, 1701; P. M.
Weintraub, J. S. Sabol, J. M. Kane and D. R. Borcherding, Tetrahedron,
2003, 59, 2953.
2 S. G. Davies and O. Ichihara, Tetrahedron: Asymmetry, 1991, 2, 183.
3 For a review of this area, see: S. G. Davies, A. D. Smith and P. D. Price,
Tetrahedron: Asymmetry, 2005, 16, 2833.
+
+
=
170.0 (C(2) O, CO2C(Me)3 and CO2Et); m/z APCI 424.2 (MH ,
5%), 446.0 (MH+, 100%), 368.1 (MH+ − C4H8, 20%); HRMS (CI+)
C25H30NO5 requires 424.2124; found 424.2126.
4 S. G. Davies and I. A. S. Walters, J. Chem. Soc., Perkin Trans. 1, 1994,
1129; S. G. Davies, O. Ichihara and I. A. S. Walters, J. Chem. Soc.,
Perkin Trans. 1, 1994, 1141.
5 M. E. Bunnage, S. G. Davies and C. J. Goodwin, J. Chem. Soc., Perkin
Trans. 1, 1993, 1375; M. E. Bunnage, A. N. Chernega, S. G. Davies
and C. J. Goodwin, J. Chem. Soc., Perkin Trans. 1, 1994, 2373; M. E.
Bunnage, A. J. Burke, S. G. Davies and C. J. Goodwin, Tetrahedron:
Asymmetry, 1994, 5, 203.
6 For the use of lithium N-benzyl-N-trimethylsilylamide as a nucleophile
in conjugate addition reactions and elaboration of enolates using this
methodology, see: N. Asao, T. Uyehara and Y. Yamamoto, Tetrahedron,
1988, 44, 4173; T. Uyehara, N. Asao and Y. Yamamoto, J. Chem. Soc.,
Chem. Commun., 1989, 753; N. Asao, T. Shimada, N. Tsukada and Y.
Yamamoto, Tetrahedron Lett., 1994, 45, 8425; Y. Yamamoto, N. Asao
and T. Uyehara, J. Am. Chem. Soc., 1992, 114, 5427.
Preparation of 1-tert-butyl-5-ethyl (2S,3S,1ꢀR,aS)-2-[1ꢀ-phenyl-1ꢀ-
(N-benzyl-N-a-methylbenzylamino)methyl]-3-phenyl-4-
ethoxycarbonyl-pentanedioate 36
Following Representative procedure 1, LDA (2.0 M, 0.53 mmol,
0.27 ml), 11 (200 mg, 0.48 mmol) in THF (5 ml) and diethyl
benzylidenemalonate (120 mg, 0.48 mmol) in THF (2 ml) gave, af-
ter purification by column chromatography on silica gel (hexane–
Et2O 10 : 1), 36 (105 mg, 33%) as a colourless oil and as an
inseparable 8 : 1 mixture with diethyl benzylidenemalonate; vmax
=
(film) 2977 (C–H), 1754, 1731 (C O), 1140 (C–O); dH (400 MHz,
CDCl3) 0.68 (3H, t, J7.3, OCH2CH3), 1.13 (3H, d, J6.8, C(a)Me),
1.28 (3H, t, J7.3, OCH2CH3), 1.66 (9H, s, CO2C(Me)3), 3.42
(1H, AB, J14.9, NCHA), 3.51 (1H, AB, J14.9, NCHB), 3.54–3.61
(2H, m, C(3)H and C(2)H), 3.64–3.69 (2H, m, OCH2CH3), 3.89
(1H, d, J12.2, C(4)H), 4.06 (1H, d, J11.5, C(1ꢀ)H), 3.98 (1H, q,
J6.8, C(a)H), 4.14–4.23 (2H, m, OCH2CH3), 7.08–7.33 (20H, m,
Ph); dC (50 MHz, CDCl3) 13.4, 14.0, 19.9 (OCH2CH3 × 2 and
C(a)Me), 28.2 (CO2C(Me)3), 44.1, 49.4 (C(3)H and C(2)H), 51.2
(NCH2), 56.1 (C(4)H), 61.1, 61.6 (OCH2CH3 × 2), 63.8 (C(1ꢀ)H),
81.0 (CO2C(Me)3), 126.0, 126.3, 127.0, 127.1, 127.2, 127.4, 127.9,
128.0, 128.8, 129.4, 130.2, 130.5 (Pho/m/p), 135.2, 135.7, 141.4, 145.1
(Phipso), 167.5, 167.8, 171.5 (CO2C(Me)3 and CO2Et × 2); m/z
APCI+ 664.3 (MH+, 100%), 686.6 (MNa+, 10%), 608.6 (MH+ −
C4H8, 5%); HRMS (CI+) C42H50NO6 requires 664.3638; found
664.3644.
7 T. Uyehara, N. Shida and Y. Yamamoto, J. Chem. Soc., Chem.
Commun., 1989, 113; N. Shida, T. Uyehara and Y. Yamamoto, J. Org.
Chem., 1992, 57, 5049; T. Uyehara, S. Tadao and Y. Yamamoto, J. Org.
Chem., 1992, 57, 3139.
8 J. G. Urones, N. M. Garridio, D. D´ıez, S. H. Dominguez and S. G.
Davies, Tetrahedron: Asymmetry, 1997, 8, 2683; J. G Urones, N. M.
Garridio, D. D´ıez, S. H. Dominguez and S. G. Davies, Tetrahedron:
Asymmetry, 1999, 10, 1637; S. G. Davies, D. D´ıez, S. H. Dominguez,
N. M. Garrido, D. Kruchinin, P. D. Price and A. D. Smith, Org. Biomol.
Chem., 2005, 3, 1284.
9 For related Michael-initiated ring-closure reactions, see: R. D. Little
and J. R. Dawson, Tetrahedron Lett., 1980, 21, 2609; E. Yoshii, K.
Hori, K. Nomura and K. Yamaguchi, Synlett, 1995, 568; K. Takeda,
N. Ohkawa, K. Hori, T. Koizumi and E. Yoshii, Heterocycles, 1998,
47, 277; M. Ihara, M. Suzuki, K. Fukumoto and C. Kabuto, J. Am.
Chem. Soc., 1990, 112, 1164, and references therein. For a review, see:
C. Thebtaranonth and Y. Thebtaranonth, Tetrahedron, 1990, 46, 1385.
10 M. E. Bunnage, S. G. Davies, P. M. Roberts, A. D. Smith and J. M.
Withey, Org. Biomol. Chem., 2004, 2, 2763.
11 M. Yamaguchi, M. Tsukamoto and I. Hirao, Chem. Lett., 1984, 375.
12 For the oligomerisation of methyl crotonate and intramolecular Claisen
condensation for the formation of cyclohexanones upon conjugate
addition of lithium diorganocuprates, see: T. Olsson, M. T. Rahman
and C. Ullenius, Tetrahedron Lett., 1977, 18, 75. For related approaches,
see: M. van Beylen, S. Bywater, G. Smets, M. Szwarc and D. J. Worsfold,
Preparation of (3S,4S,5S,6R)-3-ethoxycarbonyl-4,6-diphenyl-5-
tert-butoxycarbonyl-piperidin-2-one 37
Following Representative procedure 3, Pd(OH)2/C (50mg), 36
(100 mg, 0.13 mmol) in MeOH (10 ml) gave, after purification
1414 | Org. Biomol. Chem., 2007, 5, 1405–1415
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Adv. Polym. Sci., 1988, 86, 87; G. H. Posner and E. M. Shulman-Roskes,
J. Org. Chem., 1989, 54, 3514.
13 D. Lucet, S. Sabelle, O. Kostelitz, T. Le Gall and C. Mioskowski,
Eur. J. Org. Chem., 1999, 2583.
14 T. Takahashi, H. Okumoto and J. Tsuji, Tetrahedron Lett., 1984, 25,
1925; T. Takahashi, Y. Naito and J. Tsuji, J. Am. Chem. Soc., 1981, 103,
5261.
15 D. J. Dixon, S. V. Ley and F. Rodr´ıguez, Angew. Chem., Int. Ed., 2001,
40, 4763; S. V. Ley, D. J. Dixon, R. T. Guy, F. Rodr´ıguez and T. D.
Sheppard, Org. Biomol. Chem., 2005, 3, 4095.
21 It is proposed that b-keto ester 14 may arise by two alternative routes.
The first involves 1,2-addition of lithium (E)-enolate 12 to the cinna-
mate ester, followed by 1,4-conjugate addition of lithium (E)-enolate 12
and subsequent retro-Mannich reaction. Alternatively, 1,4-conjugate
addition of lithium (E)-enolate 12 to the cinnamate ester, followed by
enolate decomposition to the ketene, and subsequent reaction with
lithium (E)-enolate 12 followed by retro-Mannich reaction also leads
to b-keto ester 14.
22 The absolute configuration of the major diastereoisomeric product 15
was assigned by analogy to 13; the configuration of the minor product
diastereoisomer was not unambiguously identified.
16 S. Hanessian, A. Gomtsyan, A. Payne, Y. Herve´ and S. Beaudoin, J. Org.
Chem., 1993, 58, 5032; S. Hanessian and A. Gomtsyan, Tetrahedron
Lett., 1994, 35, 7509.
23 S. Masamune, W. Choy, J. S. Petersen and L. R. Sita, Angew. Chem.,
Int. Ed. Engl., 1985, 24, 1.
17 S. G. Davies, A. D. Smith and A. R. Cowley, Synlett, 2004, 1957.
18 R. E. Ireland, R. H. Mueller and A. K. Willard, J. Am. Chem. Soc.,
1976, 98, 2868.
19 The absolute configuration of the minor diastereoisomer remains
unknown.
20 Hydrogenolysis of b-keto-ester 14 furnished (2R,3S,4S,6S)-2,4-
diphenyl-3-tert-butoxycarbonyl-6-(methyl tert-butoxycarbonyl)piper-
idine 54 in >90% crude d.e., and in 67% yield and >95% d.e. upon
purification. The relative configuration within 54 was confirmed by 1H
NOE difference experiments, with the absolute configuration derived
from the known (2R) configuration derived from (3R,aS)-11.
24 The absolute configurations within the product diastereoisomers
arising from the mismatched case were not unambiguously identified.
25 E. Nicola´s, K. C. Russell and V. H. Hruby, J. Org. Chem., 1993, 58,
766.
26 S. G. Davies and H. J. Sanganee, Tetrahedron: Asymmetry, 1995, 6, 671.
For other uses of SuperQuat oxazolidinone auxiliaries in synthesis, see:
S. G. Davies, R. L. Nicholson and A. D. Smith, Synlett, 2002, 1637; S. D.
Bull, S. G. Davies, R. L. Nicholson, H. J. Sanganee and A. D. Smith,
Org. Biomol. Chem., 2003, 1, 2886; S. G. Davies, I. A. Hunter, R. L.
Nicholson, P. M. Roberts, E. D. Savory and A. D. Smith, Tetrahedron,
2004, 60, 7553; S. G. Davies, R. L. Nicholson and A. D. Smith, Org.
Biomol. Chem., 2004, 2, 3385; S. G. Davies, R. L. Nicholson and A. D.
Smith, Org. Biomol. Chem., 2005, 3, 348.
27 S. G. Davies, G. J. Hermann, M. J. Sweet and A. D. Smith, Chem.
Commun., 2004, 1128.
28 For a review of the capability of lithium dialkylamides to act as reducing
agents, see: M. Majewski and D. M. Gleave, J. Organomet. Chem., 1994,
470, 1. See also: G. Wittig, H.-J. Schmidt and H. Renner, Chem. Ber.,
1962, 95, 2377; G. Wittig and H.-D. Frommeld, Chem. Ber., 1964, 97,
3541.
29 For a related reaction, see: B. A. Feit, U. Melamed, R. R. Schmidt and
H. Speer, J. Chem. Soc., Perkin Trans. 1, 1981, 1329.
30 Crystallographic data (excluding structure factors) has been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 240141, see: S. G. Davies, A. D. Smith and
A. R. Cowley, Synlett, 2004, 1957.
31 Probably the most successful of these are (a) the topological approach
by D. Seebach and J. Gol´ınski, Helv. Chim. Acta, 1981, 64, 1413; and
(b) that of D. A. Oare and C. H. Heathcock, Top. Stereochem., 1989,
19, 227.
32 Evidence has been presented for the existence of lithium eno-
late aggregates both in the solid state and in solution; for a re-
view, see: D. Seebach, Angew. Chem., Int. Ed. Engl., 1988, 27,
1624.
33 For a review, see: R. W. Hoffmann, Chem. Rev., 1989, 89, 1841.
34 M. Yamaguchi, M. Tsukamoto, S. Tanaka and I. Hirao, Tetrahedron
Lett., 1984, 25, 5661.
35 P. W. Betteridge, J. R. Carruthers, R. I. Cooper, C. K. Prout and D. J.
Watkin, CRYSTALS, issue 11, Chemical Crystallography Laboratory,
University of Oxford, UK, 2001.
Reagents and conditions: (i) Pd(OH)2/C, MeOH.
Preparation of (2R,3S,4S,6S)-2,4-diphenyl-3-tert-butoxycarbonyl-6-
[(tert-butoxycarbonyl)methyl]piperidine 54: Following Representative
procedure 3, Pd(OH)2/C (50 mg) and 14 (100 mg, 0.15 mmol) in MeOH
(5 ml) gave, after purification by column chromatography on silica gel
(hexane–Et2O 2 : 1), 54 as a white solid (45 mg, 67%); vmax (KBr) 3432
23
=
(N–H), 2925, 2850 (C–H), 1725, 1695 (C O), 1153 (C–O); [a]D +12.3
(c 1.0, CHCl3); dH (500 MHz, CDCl3) 0.83, 1.48 (2 × 9 H, s, OC(Me)3),
1.81 (1H, app dt, J5ax,5eq12.8, J5ax,4;5ax,63.1, C(5)Hax), 2.14 (1H, br s, NH),
ꢀ
ꢀ
ꢀ
2.28 (1H, app q, J12.7, C(5)Heq), 2.55 (1H, dd, J1 A,1 B15.0, J1 A66.6,
C(1ꢀ)HA), 2.68 (1H, dd, J1 B,1 A15.0, J1 B,66.8, C(1ꢀ)HB), 3.05 (1H, app
t, J4.2, C(3)H), 3.21–3.29 (2H, m, C(4)H and C(6)H), 4.19 (1H, d,
J3.5, C(2)H), 7.18–7.36 (10H, m, Ph); dC (100 MHz, CDCl3) 27.4, 28.1
(2 × OC(Me)3), 30.8 (C(5)H2), 43.1 (C(1ꢀ)H2), 44.6 (C(3)H), 51.7, 54.2
(C(4)H and C(6)H), 62.0 (C(2)H2), 79.7, 80.5 (2 × OC(Me)3), 126.3,
126.5, 126.8, 127.5, 127.9, 128.2 (Pho/m/p), 141.2, 142.5 (Phipso), 171.0,
171.5 (2 × CO2C(Me)3); m/z APCI+ 452.0 (MH+, 100%), 474.3 (MNa+,
30%), 396.3 (MH+ − C4H8, 50%); HRMS (CI+) C28H38NO4 requires
452.2789; found 452.2800.
ꢀ
ꢀ
ꢀ
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 1405–1415 | 1415
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