Beyond classical reactivity patterns: Shifting from 1,4- to 1,6-additions in regio- and enantioselective organocatalyzed vinylogous reactions of olefinic lactones with enals and 2,4-dienals

Article abstract of DOI:10.1021/ja4029928

Organocatalysis is shown to expand the classical reactivity pattern for conjugate addition reactions. It is demonstrated that the site selectivity can be extended from 1,4- to 1,6-additions for the enantioselective vinylogous additions of methyl-substituted vinylogous lactones to enals and 2,4-dienals. This novel reactivity is demonstrated for methyl-substituted olefinic azlactones and butyrolactones. Their synthetic potential is first highlighted by the development of the organocatalytic regioselective vinylogous 1,4-addition to enals which proceeds with a very high level of double-bond geometry control and excellent enantioselectivity. The concept is developed further for the unprecedented intermolecular enantioselective organocatalyzed vinylogous 1,6-addition to linear 2,4-dienals, by which the site selectivity of the process is extended from the β-position to the remote δ-position of the 2,4-dienal. The organocatalyst controls the newly generated stereocenter six bonds away from the stereocenter of the catalyst with a high level of enantiocontrol, and the products are obtained with full control of double-bonds configuration. The scope of these new reaction concepts is demonstrated for a series of aliphatic and aryl-substituted enals and 2,4-dienals undergoing enantioselective vinylogous reactions with methyl-substituted olefinic azlactones and butyrolactones. Furthermore, mechanistic considerations are presented which can account for the change from 1,4- to 1,6-selectivity. Finally, a number of different transformations of the optically active 1,4- and 1,6-addition products are demonstrated.

Full text of DOI:10.1021/ja4029928

Article
pubs.acs.org/JACS
Beyond Classical Reactivity Patterns: Shifting from 1,4- to 1,6-
Additions in Regio- and Enantioselective Organocatalyzed
Vinylogous Reactions of Olefinic Lactones with Enals and 2,4-Dienals
Luca Dell’Amico, Łukasz Albrecht, Tricia Naicker, Pernille H. Poulsen, and Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus University, DK-8000 Aarhus C, Denmark
S
* Supporting Information
ABSTRACT: Organocatalysis is shown to expand the classical
reactivity pattern for conjugate addition reactions. It is
demonstrated that the site selectivity can be extended from
1,4- to 1,6-additions for the enantioselective vinylogous
additions of methyl-substituted vinylogous lactones to enals
and 2,4-dienals. This novel reactivity is demonstrated for
methyl-substituted olefinic azlactones and butyrolactones.
Their synthetic potential is first highlighted by the development
of the organocatalytic regioselective vinylogous 1,4-addition to
enals which proceeds with a very high level of double-bond
geometry control and excellent enantioselectivity. The concept is developed further for the unprecedented intermolecular
enantioselective organocatalyzed vinylogous 1,6-addition to linear 2,4-dienals, by which the site selectivity of the process is
extended from the β-position to the remote δ-position of the 2,4-dienal. The organocatalyst controls the newly generated
stereocenter six bonds away from the stereocenter of the catalyst with a high level of enantiocontrol, and the products are
obtained with full control of double-bonds configuration. The scope of these new reaction concepts is demonstrated for a series
of aliphatic and aryl-substituted enals and 2,4-dienals undergoing enantioselective vinylogous reactions with methyl-substituted
olefinic azlactones and butyrolactones. Furthermore, mechanistic considerations are presented which can account for the change
from 1,4- to 1,6-selectivity. Finally, a number of different transformations of the optically active 1,4- and 1,6-addition products are
demonstrated.
Scheme 1. Previous HOMO-Rising Strategies Involving
Olefinic Azlactones
INTRODUCTION
■
The concept of vinylogy, originally introduced by Fuson,1 has
been applied to a wide range of reactions, such as the aldol,
Mannich, and Michael reactions as well as Diels−Alder
cycloadditions.2 In the field of enantiocatalytic reactions
significant advances have been made owing to the introduction
of chiral metal complexes3 and the availability of a large variety
of silyl dienolates as stable vinylogous nucleophiles.4 The
attention has also recently been focused on the development of
organocatalyzed vinylogous reactions.5 In this area different
catalytic strategies have been applied, such as chiral bases or
acids,6 and bifunctional, cinchona alkaloid-based, H-bond
directing catalysts.7
We envisioned the possibility to alter the classical reactivity
of the olefinic system by introducing a methyl-substituent to
the exocyclic double bond. It was anticipated that a reaction of
such a system with a base might result in HOMO-rising,
thereby promoting a reaction with the LUMO of an α,β-
unsaturated aldehyde (enal), activated via iminium-ion
formation. In this manner, it was assumed to reverse the
previously reported reactivity patterns (Scheme 2). Further-
more, it was the goal that this concept could be further
Organocatalysts, such as primary or secondary amines, have
been introduced as electrophilic enhancers or nucleophilic
activators via iminum-ion or enamine formation, respectively.8
The evolution of this concept has resulted in the development
of dienamines,8,9 trienamines,8,10 and cross-trienamines8,11 as
vinylogous and hypervinylogous nucleophilic systems. Recently,
it was demonstrated that Z-olefinic azlactones can react as
dienophiles in a [4 + 2]-Diels−Alder-type cycloaddition either
with trienamines or cross-trienamines via an interaction
between the HOMO of these systems with the LUMO of the
azlactones, in the presence of a silyl-protected diarylprolinol
catalyst (Scheme 1).10c,11
Received: March 30, 2013
© XXXX American Chemical Society
A
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products must be controlled, as a mixture of Z- and E-isomers
can potentially be formed.
Scheme 2. Novel Organocatalytic Vinylogous Michael-Type
Reaction Between Enals and Olefinic Lactones
Herein, we present the first organocatalyzed vinylogous
Michael-type addition of methyl-substituted olefinic azlactones
and butyrolactones to aromatic and aliphatic enals. These
additions proceed with full γ′-selectivity and very high double-
bond configuration control and enantioselectivity. Moreover,
we introduce a series of unprecedented examples of conjugated
iminium-ion mediated 1,6-additions between methyl-substi-
tuted olefinic azlactones and butyrolactones and linear 2,4-
dienals. Importantly, no substituents in the 2,4-dienals are
required to guide the regioselectivity of the process to the
remote electrophilic position and the reaction proceeds with
virtually complete δ-selectivity. This enantioselective carbon−
carbon bond forming reaction can be assumed as the first
organocatalyzed doubly vinylogous Michael-type addition and
the first direct enantioselective 1,6-addition to 2,4-dienals.
extended by replacing the nitrogen atom in the β-position of
azlactone moiety with a carbon atom, thus obtaining a methyl-
substituted olefinic butyrolactones as a new class of vinylogous
pronucleophiles, potentially possessing the same vinylogous
reactivity.
At this stage several challenges have to be addressed. First,
the regioselectivity must be considered because of the
polynucleophilic nature of the dienolates employed. It has
been demostrated that α-substituted azlactones can react in the
α-position with electrophilic reagents including enals12 or in the
γ-position with acyl phosphonates.13 In a similar manner, γ-
phenyl-substituted butenolides prefer to react at the γ-carbon
atom with various Michael acceptors.14 In the present case the
vinylogous nucleophile can react at three different positions
(α:γ:γ′) thereby further increasing the complexity of the
possible reaction pathways. Second, the configuration of the
exocyclic double bond in the product has to be controlled. It
should be noted that the geometry of the double bond in the
starting compound is lost during the formation of the dienolate
species. Moreover, with the azlactone nucleophiles, the starting
material is an inseparable mixture of the Z- and E-isomers in
various ratios.
RESULTS AND DISCUSSION
■
Michael-Type Addition of Vinylogous Olefinic Azlac-
tone Nucleophiles to Enals. The 2-substituted oxazol-5-
(4H)-ones, commonly known as azlactones, are useful reagents
for the introduction of an amino acid moiety in molecules
avoiding some of the drawbacks which can be caused by using
classical peptide chemistry.17 Furthermore, the azlactone is a
flexible moiety in diversity oriented synthesis18 due to the
concomitant presence of two orthogonal reactive sites and for
the easy accessibility from cheap and readily available
compounds.19 Therefore, the use of azlactones as building
blocks in the field of organocatalysis constitutes an important
tool in modern asymmetric synthesis.17
Studies were initiated by testing the feasibility of the olefinic
azlactone 1a with the methyl group attached to the olefinic
moiety for nucleophilic attack to cinnamaldehyde 2a. The
addition was performed in the presence of 20 mol % of the
TMS-protected diphenylprolinol catalyst 4 in CH2Cl2.
Disappointingly, no reaction occurred, and complete recovery
of the starting materials was observed (Table 1, entry 1). It was
anticipated that the addition of a catalytic amount of base might
facilitate the dienolate formation thereby enabling the novel
reactivity pattern. Triethylamine was chosen as a base in the
initial screening. Gratifyingly, the formation of the desired
vinylogous adduct 3a was achieved, albeit in a moderate yield
(35%), 3:1 ratio between Z- and E-isomers and 70% ee for the
major isomer (entry 2). In order to facilitate the catalyst
turnover, 3 equiv of water were added. This turned out to be a
useful solution, not only improving the yield of 3a but also
increasing the Z:E ratio to 4:1 and the enantioselectivity to 85%
ee (entry 3). Employment of 1 equiv of the base instead of a
catalytic amount resulted in better yield and Z:E selectivity
although provided lower enantiocontrol (entry 4).
Subsequently, an even more intriguing goal was envisioned,
namely, the employment of 2,4-dienals rather than enals as the
electrophilic counterpart which also adds further challenges.
First, the competition between 1,4- (classical Michael) and 1,6-
additions (vinylogous Michael) (Scheme 3). Typically, the 1,4-
Scheme 3. Unprecedented Organocatalytic Doubly
Vinylogous Michael-Type Reaction Between 2,4-Dienals and
Alkylidene Lactones
The screening of the catalysts revealed that only the
diphenylprolinol catalysts 4 and 5 with different silyl protecting
groups could be successfully employed in the transformation
(entries 3, 5). In the presence of the TMS-protected
diarylprolinol 6, very poor yield of 3a was obtained (entry
6), and the H-bond directing catalyst 7 proved to be unable to
control the stereochemical outcome of the reaction (entry 7).
By replacing the water with brine, the yield of 3a was increased
to 71% without alteration of the regio- and enantioselectivity
(entry 8).20 Changes in the solvents and bases did not improve
the results in terms of yield and regioselectivity (entry 9−12).
Interestingly, in the presence of stronger organic bases the
addition is favored over the 1,6-addition,15 and only few
examples of enantio- and regioselective 1,6-additions are
known.16 The 1,6-addition reaction of 2,4-dienals remains an
important task and still is an unexplored field of research,
particularly when stereoselective transformations are consid-
ered.16e Second, the enantiocontrol of the new δ-stereocenter
which is six bonds away from the stereocenter of the catalyst is
another important challenge that must be addressed. Finally,
the geometry of the second conjugated double bond in the
B
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Table 1. Michael-Type Addition of Vinylogous Olefinic
Azlactone 1a to Cinnamaldehyde 2a Screening Results
Table 2. Scope of the Michael-Type Addition of Vinylogous
Olefinic Azlactones 1 to Enals 2
a
a
b
c
d
entry
1
R (2)
3
yield (%)
Z:E
ee (%)
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1c
C6H5 (2a)
p-OMeC6H4 (2b)
p-ClC6H4 (2c)
o-ClC6H4 (2d)
1-naphthyl (2e)
furyl (2f)
3a
3b
3c
3d
3e
3f
75
62
58
66
63
60
57
72
77
7:1
6:1
98
96
93
97
93
90
94
92
>99
5:1
b
c
d
entry
cat
solvent
base
yield (%)
Z:E
ee (%)
11:1
5:1
1
2
4
4
4
4
5
6
7
5
5
5
5
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
−
−
35
55
58
58
5
−
−
70
85
77
95
−
−25
95
93
83
97
−
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
DIPEA
NaOAc
3:1
4:1
6:1
5:1
−
3:1
5:1
4:1
2:1
3:1
3:1
5:1
e
3
n-pentyl (2g)
2a
3g
3h
3i
10:1
5:1
e
,
f
4
e
e
e
g
5
2a
5:1
6
7
8
a
Reactions were performed at 0.2 mmol scale in CH2Cl2 (0.2 M) (see
b
c
73
71
69
60
50
33
Supporting Information). Isolated yield. Z:E ratio as determined by
d
1H NMR analysis of the crude reaction mixtures. Enantiomeric excess
g
was determined by UPC.2
9
g
g
g
10
11
12
THF
CH2Cl2
CH2Cl2
groups were introduced on the exocyclic aromatic ring in 1 to
elucidate the role of the olefinic phenyl ring in this
transformation. Methyl- and iodo-substituted aromatic systems
gave analogous performance. In particular, in these cases very
high levels of regio- and enantiocontrol were obtained (entries
8, 9).
a
Reactions were performed at 0.05 mmol scale in CH2Cl2 (0.2 M)
using 1a (1 equiv) and 3a (3 equiv) (see Supporting Information).
b
c
Isolated yield. Z:E ratio was determined by 1H NMR analysis of the
d
crude reaction mixture. Enantiomeric excess was determined by
UPC.2 0.15 mmol of water was used. 1 equiv of NEt3 was used. 0.15
e
f
g
Michael-Type Addition of Vinylogous Olefinic Butyr-
olactones to Enals. The butenolide skeleton plays a
prominent role in synthetic organic chemisty because of its
presence as a pharmacophore in a number of natural products
and synthetic or semisynthetic drugs.24 The utilization of the
butenolide moiety has been associated with the construction of
the related silyl dienolate nucleophiles and their applications in
vinylogous Mukaiyama addition reactions.2,25 Importantly, in
the past few years enantioselective versions of this reaction
were successfully developed.25c−g Furthermore, γ-substituted
butenolide units have also received considerable interest in
organocatalysis, and a number of new methodologies were
efficiently introduced.2,5a Usually, the in situ formed dienolate
reacts with different electrophiles in the γ-position. In order to
alter and expand the common reactivity profile of this
important class of nucleophiles, we decided to apply the
previously optimized conditions to the butyrolactone counter-
parts.
To our delight, the initial screening showed that the methyl-
substituted olefinic butyrolactone 8a was a promising candidate
as a vinylogous nucleophile reacting in the γ′-position instead
of the other electron-rich carbon atoms. Furthermore,
compound 8a proved to be more selective and reactive than
the corresponding azlactone 1a. Therefore, in order to improve
the enantioselectivity we decided to employ a stronger base,
such as DIPEA, which exhibited lower reactivity in the
azlactone screening, although provided better enantiocontrol
(see Table 1, entry 10). The reaction between cinnamaldehyde
2a and 8a afforded excellent results (Table 3, entry 1). All the
positions in the aromatic ring were tested (entries 2−5), and
the reactions proceeded with the formation of only one isomer
mmol of brine was used.
enantioselectivity was increased to 97% ee, albeit lower yield
was observed (entry 11).21
With the optimized reaction conditions in hand, the
generality of the vinylogous Michael addition with respect to
both the olefinic substituents 1 and enals 2 was tested. In order
to evaluate the disclosed methodology a higher scale was
applied (0.2 mmol). Interestingly, better regio- and enatiocon-
trol were observed, and a slightly better yield was achieved
when compared to the previous result (Table 1, entry 8 vs
Table 2, entry 1).22
Both electron-donating and -withdrawing substituents in the
para-position of the aromatic ring in the enals 2a,b were well
tolerated in the transformation providing the desired products
3b,c with high regiocontrol and excellent enantioselectivity
(Table 2, entries 2, 3). Moving the substituent to the ortho-
position of the aromatic ring in the enal proved to be beneficial
for the control of the geometry of the double bond in the
product 3d, and 97% ee was obtained (entry 4). Not only the
presence of the phenyl rings afforded good results but also
naphthyl and furyl substituents in the β-position of the enals
were well tolerated (entries 5, 6). Even less reactive aliphatic
aldehydes were successfully employed as demonstrated for the
commercially available trans-2-octenal 2g, which turned out
fully compatible in the direct vinylogous Michael addition
(entry 7).
With the positive results obtained for the enals 2 as the
electrophilic system, the attention was turned to the reactivity
of different nucleophiles.23 Electron-donating and -withdrawing
C
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Table 3. Scope of the Michael-Type Addition of Vinylogous
Olefinic Butyrolactones 8 to Enals 2
Table 4. Scope of the Doubly Vinylogous Michael-Type
Addition of Olefinic Lactones to 2,4-Dienals
a
b
c
d
entry
8
R (2)
9
yield (%)
E:Z
ee (%)
1
2
3
4
5
6
7
8
9
8a
8a
8a
8a
8a
8a
8a
8b
8c
C6H5 (2a)
p-OMeC6H4 (2b)
p-ClC6H4 (2c)
o-ClC6H4 (2d)
1-naphthyl (2e)
furyl (2f)
9a
9b
9c
9d
9e
9f
86
75
86
89
91
73
25
63
77
>20:1
>20:1
>20:1
>20:1
>20:1
10:1
98
90
95
95
93
91
97
92
97
n-pentyl (2g)
2a
9g
9h
9i
>20:1
>20:1
>20:1
2a
a
Reactions were performed at 0.2 mmol scale in CH2Cl2 (0.2 M) (see
b
c
Supporting Information). Isolated yield. E:Z ratio was determined by
d
1H NMR analysis of the crude reaction mixture. Enantiomeric excess
was determined by UPC.2
9 with excellent enantioselectivity (90−98% ee). The furyl-
substituted enal 2f also gave excellent results (entry 6). trans-2-
Octenal 2g was chosen as an aliphatic enal, and analogous
results in terms of stereoselectivities were obtained; albeit lower
yield of the addition product 9g was obtained (entry 7) (vide
infra).
Further studies revealed that the presence of electron-
donating and -withdrawing groups on the exocyclic aromatic
ring in 8 were well tolerated in the reaction. With both
substituents high level of regio- and enatiocontrol were
achieved (Table 3, entries 8, 9).
a
Reactions were performed at 0.1 mmol scale in CH2Cl2 (0.2 M) (see
b
c
Supporting Information). Isolated yield. Z:E and E:Z ratios were
determined by 1H NMR analysis of the crude reaction mixture.
d
Enantiomeric excess was determined by UPC.2
the newly generated δ-stereocenter in the vinylogous iminium-
ion activated 2,4-dienal species. The reaction proceeded slower,
but similar yields comparable to the 1,4-addition were obtained.
Both methyl-substituted olefinic azlactones and butyrolactones
were found to be useful substrates for the transformation, and
different δ-substituted 2,4-dienals were evaluated to demon-
strate the generality of the reaction. Methyl, propyl, and hexyl
groups were found to be suitable as remote substituents. In all
cases, high level of enantio- and regiocontrol were obtained
(Table 4). The geometry of both exocyclic double bonds in the
products 11 was fully controlled in all of the cases.
Interestingly, the 1,6-selectivity turned out to be dependent
on the nature of the substituent in the 6-position of the 2,4-
dienal. When a phenyl group was introduced in this position
((2E,4E)-5-phenylpenta-2,4-dienal 10d), the reactions with the
methyl-substituted olefinic azlactone 1a and butyrolactone 8a
proceeded with low site-selectivity. In those cases a mixture of
1,4- and 1,6-addition products were obtained (Scheme 4) (for
further discussion see Mechanistic Considerations below).
Mechanistic Considerations. The screening studies
revealed that the presence of a base was crucial for the reaction
(see Table 1 and Supporting Information). It is assumed that
the base acts as a dual activator: First, it is involved in a classical
acid−base reaction with the methyl-substituted olefinic
azlactone 1 or butyrolactone 8, which results in the in situ
formation of the vinylogous dienolate species 12. Together
with the formation of 12, the conjugated acid is formed, which
is proposed to promote the condensation between catalyst 5
The absolute configuration of the stereocenter being formed
was assigned to be (S) based on the X-ray structure of 15a (vide
infra). The absolute configuration of the other products were
assigned by the analogy.26
Doubly Vinylogous Michael-Type Addition of Olefinic
Az- And Butyrolactones to 2,4-dienals. The vinylogy
concept is a milestone in modern organic chemistry.1,2
However, its applicability can be a challenge, such as for the
nucleophilic addition to the remote position when two or more
double bonds are in conjugation with an electron-withdrawing
group.15 Nowadays, the vinylogous Michael reaction, or 1,6-
addition to 2,4-dienals, still remains a challenging task in
organocatalysis, and to the best of our knowledge, no examples
of intermolecular enantioselective approaches have been
reported.
In order to extend the generality and the potential of the
disclosed methodology, we decided to apply the general
conditions developed to linear 2,4-dienals. We initiated our
investigation by applying the optimized conditions for the 1,4-
addition to the reaction between the methyl-substitued olefinic
azlactone 1a and hexadienal 10a. Remarkably, the 1,6-addition
occurred exclusively and proceeded with a full δ-selectivity.
Importantly, the nucleophile reacted also with complete
regiocontrol from the γ′-position (Table 4). To our delight,
high level of enantiocontrol was obtained, despite the long (six
bonds) distance between the stereocenter of the catalyst and
D
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Mechanistic aspects of the developed methodologies related
to reactivity and regioselectivity of the processes are worth a
special emphasis. Notably, calculations of the LUMO
coefficients of the vinylogous iminium-ion intermediate can
not be used to unambiguously rationalize the observed site
selectivity. Therefore, it is postulated that an interaction
between the negatively charged oxygen atom in the vinylogous
dienolate species and the positively charged nitrogen atom of
the iminium-ion intermediate is important for the outcome of
the reaction. This interaction is proposed to be responsible for
the proper alignment of the β-carbon atom of the iminium-ion
intermediate with regard to the γ′-position of the dienolate
intermediate and accounts for very high site-selectivity observed
(Scheme 6, TS A). Furthermore, the π-stacking interaction
between the β-aryl group of enal and β′-aryl moiety of dienolate
is proposed to be an important factor, stabilizing the transition
state of the 1,4-addition. However, in the case of alkyl
substituted enals, the same alignment of the substrate results in
a less-favorable interaction between the alkyl chain of the enal
and the γ′-aryl moiety of the lactone counterpart. The reaction
can proceed as proposed in Scheme 6, TS B, which accounts for
the lower reactivity, especially pronounced in the case of the
reaction of aliphatic enals and the butyrolactone-based
substrate 8a (Table 3, entry 7). The system can also, in
order to avoid such adverse steric interaction, position the
dienolate intermediate further away from the iminium-ion
intermediate placing the reactive centers apart (Scheme 6, C).
This alignment of reaction partners can also be accounted for
the diminished reactivity of the aliphatic enal (Table 3, entry 7).
Interestingly, such a separating effect is beneficial for the
developed 1,6-addition. In this case, it is proposed that the
reaction proceeds via transition state D in Scheme 6 (with the
alignment of reactants related to C rather than A/B) in order to
avoid unfavorable steric interactions. In such a manner, the γ′-
position of the dienolate species is situated in the spatial
proximity to the δ-carbon atom of the vinylogous iminium-ion
intermediate resulting in a regioselective 1,6-addition. In this
context it is worth noticing that for the δ-phenyl substituted
2,4-dienal the π-stacking interaction can again be present, which
places both reaction partners closer and forces the reaction to
proceed through transition state E as outlined in Scheme 6.
This merging interaction is proposed to be responsible for the
low site-selectivity observed in that case as both β- and δ-
carbon atoms of the vinylogous iminium-ion are positioned in a
similar distance with regard to the γ′-position of the dienolate
intermediate.
Scheme 4. 1,4- vs 1,6-Selectivity in the Reaction of (2E,4E)-
5-Phenylpenta-2,4-dienal 10d with the Methyl-Substituted
Olefinic Lactones
and enal 2 to give the iminium-ion intermediate 13 (Scheme
5). Based on these considerations, it is assumed that the
Scheme 5. Proposed Organocatalytic Cycle for the
Vinylogous 1,4-Addition of Olefinic Azlactones or
Butyrolactones to Enals
combination of the catalyst and base can efficiently cooperate,
when the simultaneous in situ formation of the nucleophilic
counterpart is necessary. With the formation of 13, the
products 3 or 9 are accessed via a classical iminium-ion-
mediated catalytic cycle. This hypothesis was further proved by
the fact that the reaction yield was improved by employing 1
equiv of the base (Table 1, entry 4).
The geometry of the double bond in the methyl-substituted
olefinic azlactone 1 is lost during the formation of the
vinylogous dienolate species 12. Starting from a mixture of
the Z- and E-isomers of 1, a Z:E-ratio of up to 11:1 was
obtained in product 3. The configuration of the olefinic lactone
moiety, both in the 1,4- and 1,6-addition products 3, 9 and 11,
was unambiguously assigned by 2D-NOESY NMR experi-
ments.
It is proposed that the stereochemical outcome of the
vinylogous additions using both enals and 2,4-dienals is
controlled by the shielding effect of the TBS-protected prolinol
catalyst 5. Therefore, the vinylogous methyl-substituted olefinic
azlactone or butyrolactone nucleophiles attack from the side
opposite to the steric bulk of the catalyst.
A final observation concerning the 1,6-addition of methyl-
substituted olefinic lactones to 2,4-dienals was made.
Interestingly, when the same conditions for the vinylogous
1,6-addition were applied to a nonvinylogous azlactone
nucleophile, no reaction was observed, and complete recovery
of the starting materials was achieved (Scheme 7). This
behavior can be explained by different interactions between the
nucleophile and the 2,4-dienal. In the vinylogous 1,6-addition a
superimposition of the HOMO in the methyl-substituted
olefinic azlactone or butyrolactone and the LUMO in the
iminium-ion is achieved (see Scheme 3), whereas with a
The configuration for the enal alkene moiety in the 1,6-
addition product 11b was determined to be E based on the
coupling constants present in the 1H NMR spectrum.
Furthermore, the NOESY interactions confirmed this config-
uration.
E
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Scheme 6. Rationalizations for the Observed Reactivity and Site-Selectivity Patterns
products (Scheme 8). Furthermore, only in the presented
organocatalyzed vinylogous addition to enals is it possible to
Scheme 7. Comparison Between the Vinylogous 1,6-
Addition of Olefinic Azlactone and the Nonvinylogous 1,6-
Addition of Alkyl Azlactone
Scheme 8. Transformations of the 1,4-Addition Product 3a
to Olefinic α-Amino Acid 15a and its X-ray structure
(bottom) and α-Amino Acids 16a,b
nonvinylogous nucleophile this favorable interaction is not
possible.
Product Manipulations. In order to prove the synthetic
potential of the disclosed methodology and versatility of the
optically active products obtained, we envisioned different
manipulations for both the 1,4- and 1,6-addition products.
Starting from the 1,4-addition product 3a, the opening of the
azlactone moiety was attempted, thus affording access to the
protected amino acids. The ring-opening reaction was
performed by treating 3a with MeOH under basic conditions.
The reaction furnished the desired product 15a in quantitative
yield, while the enantiomeric excess was maintained. Sub-
sequently, 15a was subjected to a reduction catalyzed by Pd/C
under H2 atmosphere (20 bar) to afford two protected amino
acids 16a and 16b in excellent yield.27 Interestingly, after the
reduction of the tetrasubstituted double bond, the aldehyde
moiety was also reduced to the corresponding alcohol. The
possibility to form three different non-natural amino acids of
which the first (15a) contained a conjugated double bond, and
the other two (16a,b) possessed three stereocenters, in a simple
two-step sequence, starting from compound 3a, highlights the
synthetic relevance of the olefinic azlactone 1,4-addition
reach the formation of two new stereocenters starting from the
amino acid 15a originating from the exocyclic double bond in
the corresponding azlactone.
The butyrolactone addition product 9a was subjected to
reduction of the endocyclic double bond under H2 atmosphere
in the presence of a catalytic amount of Pd/C to afford the
desired compound 17 with concomitant introduction of one
new stereocenter (Scheme 9).28
Finally, a transformation of the 1,6-addition products was
attempted. It was imagined to highlight the importance of these
compounds by utilizing the existing enal moiety. Therefore, the
F
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Article
Scheme 9. Transformations of the 1,4-Addition Product 9a
into Olefinic Lactone 17
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, analytical data and NMR. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
kaj@chem.au.dk
adduct 11a was subjected to an organocatalyzed epoxidation.
Initially, with the (R)-configured TMS-protected diphenylpro-
linol catalyst ent-4 was employed. The epoxide 18a was
obtained in good yield and diastereoselectivity. Interestingly, a
slightly improved enantioselectivity compared to the starting
material 11a was achieved (Scheme 10).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was made possible by grants from Aarhus University,
Carlsberg Foundation, and FNU. Thanks are also expressed to
The Dell’Amico and Calendi Foundation for supporting the
stay of L.D.A. T.N. thanks South African National Research
Foundation and Oppenheimer Memorial Trust for financial
support. Thanks are also expressed to Dr. Jacob Overgaard for
X-ray analysis.
Scheme 10. Transformations of the 1,6-Addition Product
11a to Epoxides 18a,b
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tion for details).
CONCLUSION
■
In summary, we have demonstrated the possibility to alter the
reactivity patterns of selected electrophiles, reversing the
LUMO-lowering activation into the HOMO-rising activation
by the application of organocatalysis. Both methyl-substituted
olefinic azlactones and butyrolactones showed complete
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nonvinylogous nucleophile did not show the same reactivity
in this transformation. This reveals the need of the peculiar
vinylogous characteristics in the nucleophile counterpart to
reach a perfect HOMO−LUMO interaction with the 2,4-dienal
electrophiles.
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