Direct Organocatalysed Double Michael Addition of α-Angelica Lactone to Enones

Article abstract of DOI:10.1002/ejoc.201600707

The direct vinylogous Michael addition of unactivated α-Angelica lactone to enones under iminium activation using 9-amino-9-deoxy-epi-quinine as catalyst along with 2-hydroxy-1-naphthoic acid as co-catalyst has led to the formation of γ,γ-disubstituted bu

Full text of DOI:10.1002/ejoc.201600707

DOI: 10.1002/ejoc.201600707
Full Paper
Aminocatalysis
Direct Organocatalysed Double Michael Addition of α-Angelica
Lactone to Enones
Roman Lagoutte,[a] Céline Besnard,[a] and Alexandre Alexakis*[a]
Abstract: The direct vinylogous Michael addition of unacti- drance, which would otherwise lead to the preferential forma-
vated α-Angelica lactone to enones under iminium activation tion of the syn isomer, to afford the anti isomer instead. Under
using 9-amino-9-deoxy-epi-quinine as catalyst along with 2- enamine activation, the anti isomer selectively undergoes cycli-
hydroxy-1-naphthoic acid as co-catalyst has led to the forma- sation to the hexahydrobenzofuran-2(3H)-one, which is readily
tion of γ,γ-disubstituted butenolides in high yields, moderate- separated from the left-over syn isomer. Mechanistic details, in-
to-good diastereoselectivities and excellent enantioselectivities. cluding the fate of the pro-nucleophile and the origin of the
The readily available catalytic system over-rides the steric hin- diastereoselectivity, are also discussed.
Introduction
Accessing structural complexity rapidly, efficiently and in a
highly chemo-, regio-, enantio- and diastereoselective manner
is at the forefront of organic synthesis. Developing such syn-
thetic methodologies to be operationally easy, using renewable
commercially or synthetically readily available starting materials
and catalytic systems under safe and environmentally benign
reaction conditions is of particular interest to the synthetic or-
ganic practitioner, in particular in the context of green chemis-
try. To this end, organocatalysis has emerged as a powerful tool,
which has revealed its might with the development of spectac-
ular tandem and cascade reactions under very mild conditions
to allow access to highly functionalised synthetically and bio-
logically relevant structures.[1]
Butenolides and lactones are present in around 10% of all
natural products.[2] Thus, developing synthetic approaches to
access these structures has drawn a lot of attention from the
synthetic community.[3] In 2003, MacMillan and co-workers re-
Scheme 1. Vinylogous Michael additions of α-Angelica lactone to enals (a,b)
and proposed transformation (c).
ported the first vinylogous Michael addition of α-Angelica lact-
one, activated as its silyl enol ether, to enals (Scheme 1, a).[4] In
2011, our group reported the first direct conjugate addition of
unactivated α-Angelica lactone to enals (Scheme 1, b).[5] More
recently, Pihko and co-workers proposed an approach to allow
for an extension of the scope to α-substituted enals.[6]
structurally related lactols, acetals and dihydro- and tetrahydro-
furan derivatives (Scheme 2).[7] We also anticipated that the cy-
clisation would be highly syn selective at the ring junction,[4,8]
thereby giving access to the core structure of poorly studied
natural products such as Dukunolides D–F, Granatoine, Xylo-
granatins F and H, Hainangranatumin G and Acromelact-
one A.[9] In addition, being able to control the cyclisation event
would be advantageous to access natural products structurally
related to the first conjugate addition product, such as the
Cneorins and their structural congeners.[10]
The γ-butenolide resulting from these transformations
presents an unsaturation, which we envisioned could be taken
advantage of for further cyclisation in an iminium/enamine cas-
cade reaction when using an alkyl enone partner (Scheme 1, c).
The envisioned transformation would allow access to substi-
tuted hexahydrobenzofuran-2(3H)-ones and a broad range of
[a] Department of Organic Chemistry, University of Geneva,
Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland
E-mail: alexandre.alexakis@uinge.ch
The potentially difficult tautomerisation step in the envis-
aged iminium/enamine cascade was felt not insurmountable as
comparable transformations involving Michael/Michael,[11]
Michael/aldol[12] and Michael/Mannich[13] sequences have been
reported, which encouraged us in our proposal. When this in-
http://www.unige.ch/sciences/chiorg/alexakis/group
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600707.
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Results and Discussion
Studies towards the Cascade Reaction Using a Single
Catalyst
To assess the feasibility of the reaction, a set of readily available
catalysts (Figure 1) were screened under standard conditions
(Table 1). -Proline (I; entry 1) was used for a Michael/aldol cas-
L
cade reaction of enones,[12] but it was inefficient in promoting
the desired transformation. Quinine-derived primary amine cat-
alyst II (entry 2) was found to be slightly anti-selective with
virtually perfect enantioselectivity for anti-3. A low conversion
was, however, observed, and it was unable to promote the cycli-
sation reaction. In sharp contrast, primary amine-thiourea bi-
functional catalysts IV and V (entries 3 and 4) were found to
rather efficiently promote the vinylogous Michael addition and
to a limited extent the cyclisation of anti-3 to 4.[21,22] However,
moderate enantio- and diastereoselectivities were observed.
This difference in reactivity suggested that the thiourea is es-
sential for reactivity, and we set out to reverse the diastereo-
selectivity as well as to improve the enantioselectivity.
Scheme 2. Synthetic relationship between hexahydrobenzofuranones and
hexahydrobenzofurans, and examples of structurally related natural products.
vestigation was initiated, only one conjugate addition of an α-
butenolide to enones had been reported by Huang and co-
workers.[14] Their bifunctional tertiary amine/thiourea catalyst
led to the formation of the anti isomer, but the system was
limited to aryl enones. Soon after, three other reports by
Wang,[15] Feng[16] and Lin[17] and their co-workers followed. Un-
der Lewis acid catalysis in the first two reports and Brønsted
acid catalysis for the third, only the syn conjugate adducts were
obtained, and in all cases the scope was limited to aryl enones.
Most recently, Shibasaki and co-workers reported the direct
conjugate addition of α-butenolides to α,ꢀ-unsaturated thio-
amides and one application demonstrated the possibility of ac-
cessing methyl ketones, but the syn adduct was again ob-
tained.[18] We had, however, observed that only the anti dia-
stereomer underwent cyclisation (see below), which prompted
us to pursue our study. Unfortunately, as this study was reach-
ing completion,[19] Ye and Dixon published a diastereodivergent
version of the conjugate addition that gave high yields, dia-
stereoselectivities and enantioselectivities for a broad scope of
nucleophiles and electrophiles.[20] Their report, however, did
not mention any cyclisation of their conjugate adducts, either
in situ or in a subsequent step. We herein report our results,
including some mechanistic studies, which completes their
work and may shed some light on the origin of the enantio-
and diastereoselectivities observed in their transformation.
Figure 1. Catalysts used in this study.
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Table 1. Screening of catalysts.[a]
y
Entry
Cat.
Co-cat. (amount [mol%])
Conv. [%][b]
anti-3/syn-3[b]
anti-3 ee [%][c]
syn-3 ee [%][c]
Yield 4 [%][b]
1
2
3
4
5
6
7
8
I
II
IV
V
VI
VII
VIII
IX
(S)-X
(R)-X
XI
XII
II
II
–
<1
5
–
–
99
–66
77
–
78
–67
–
80
78
65
60
99
79
44
–
–56
6
51
–
–6
–6
–
50
48
38
39
–12
26
45
–
–
8
3
–
–
–
–
8
8
–
–
–
–
–
C6H5CO2H (40)
C6H5CO2H (40)
C6H5CO2H (40)
C6H5CO2H (40)
C6H5CO2H (40)
C6H5CO2H (40)
C6H5CO2H (40)
C6H5CO2H (40)
C6H5CO2H (40)
C6H5CO2H (60)
C6H5CO2H (60)
1.6:1
1:1.1
1:2.9
–
1.1:1
1.5:1
–
1:1.2
1:1.2
1.4:1
1.4:1
2.7:1
2.1:1
1.5:1
63
83
<1
26
19
<1
86
92
42
55
45
45
54
9
10
11
12
13
14[d]
15[e]
N-Boc-
N-Boc-
N-Boc-
D
D
D
-Phg (40)
-Phg (40)
-Phg (40)
II
[a] Reactions performed in toluene (0.1 M
) at room temperature for 48 h. [b] Determined by 1H NMR and GC–MS analyses of the crude product. [c] Determined
by supercritical fluid chromatography (SFC) analysis of the product after column chromatography. [d] Catalyst XIII (40 mol%) was added. [e] Catalyst XIV
(40 mol%) was added.
Screening other solvents and co-catalysts did not lead to provement in the conversion was observed and excellent enan-
noticeable improvement,[23] and we settled on the initial reac- tioselectivity was retained (entry 13). However, the
tion conditions and screened other catalysts. The loss of reactiv- diastereoselectivity remained low, although in favour of anti-3,
ity with the Takemoto catalyst VI (entry 5) comforted us with and 4 was not observed. In contrast, negligible improvement
the idea that a primary amine is necessary for catalysis to take of the conversion was observed upon addition of thioureas XIII
place. The squaramide analogues VII and VIII, with their more or XIV, both the diastereoselectivity and the enantioselectivity
extensive hydrogen bonding, were thought to better orient the were eroded (entries 14 and 15). And again, the desired 4 was
pro-nucleophile. Although they did reverse the diastereoselect- not formed.
ivity, lower conversions were obtained, and none of the desired
We soon understood that a thiourea, contrary to what was
4 was observed. Bulky analogue IX did not catalyse the reaction initially thought, increases the rate of unwanted side-reactions,
(entry 8). In an attempt to stabilise one diastereomeric transi- which may also explain the lower diastereo- and enantioselect-
tion state, we tried the reaction with catalysts (S)-X and (R)-X ivities observed previously. Furthermore, we also felt that carry-
(entries 9 and 10). Although no match/mismatch was observed, ing out the two transformations in a single step would remain
the catalytic activity was restored, but not satisfactorily, despite illusory. To this end, we screened a broad range of co-catalysts
their ability to promote the cyclisation to a limited extent. and solvents (Table 2).[25] In the absence of an acid co-catalyst
Along the same lines, pseudo-diastereomeric catalysts XI and (entry 1), no reaction took place. The more acidic p-nitrobenzoic
XII were tested (entries 11 and 12). But again, despite the ab- acid improved neither the conversion nor the diastereoselectiv-
sence of match/mismatch and a reversed diastereoselectivity in ity, but returned a perfect enantioselectivity (entry 3). Other
favour of anti-3, loss of reactivity and lower enantioselectivity benzoic acid derivatives also failed. Gratifyingly, salicylic acid
were observed and none of the desired 4 was observed. This (entry 4) remarkably improved the conversion and the dias-
screening of ligands and conditions highlighted the need for tereoselectivity as well as maintaining a perfect enantioselectiv-
both a primary amine and a thiourea. On the other hand, ity. It even performed better than the established II/N-Boc-D-
quinine-derived catalyst II readily provided anti-3 as the major phenylglycine catalytic system (entry 5).[24] We then set out to
diastereomer and in excellent enantioselectivity. Yet, its screen different solvents. DMSO (entry 6) led to complete con-
combination with benzoic acid as co-catalyst is far from optimal version but poor diastereoselectivity, and interestingly, to com-
and combination with N-Boc-D-phenylglycine (N-Boc-D-Phg) is plete reversal of the enantioselectivity, thereby underlining the
often preferred.[24] We therefore probed the influence of this importance of tight ion-pairing in the enantiocontrol. Surpris-
well-established catalytic system in combination with thiourea ingly, the reaction was found to be rather sluggish in chlorin-
catalysts XIII and XIV. In the reaction with II and N-Boc-
D-Phg, ated solvents such as dichloromethane (entry 7). The solvent
despite the absence of a thiourea co-catalyst, a great im- screening finally revealed that aromatic solvents are preferred,
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Table 2. Optimisation of the reaction conditions.[a]
Entry
Co-cat. (amount [mol%])
Solvent
Conv. [%][b]
dr[b]
anti-3 ee [%][c]
syn-3 ee [%][c]
1
2
3
4
5
6
7
8
–
PhMe
PhMe
PhMe
PhMe
PhMe
DMSO
CH2Cl2
PhH
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
<1
5
9
1.8:1
1.6:1
1.4:1
4.9:1
2.8:1
1.3:1
3.6:1
5.9:1
nd
6.3:1
8.0:1
4.6:1
4.5:1
1.6:1
2.9:1
2.6:1
6.3:1
8.0:1
8.0:1
n.d.
99
99
99
97
–92
97
99
n.d.
99
99
99
99
n.d.
98
14
98
99
99
n.d.
–56
–13
–37
–17
74
C6H5CO2H (40)
4-NO2-C6H4CO2H (40)
2-HO-C6H4CO2H (40)
N-Boc-
2-HO-C6H4CO2H (40)
2-HO-C6H4CO2H (40)
2-HO-C6H4CO2H (40)
2-HO-C6H4CO2H (40)
2-HO-C6H4CO2H (60)
2-HO-1-naphthoic acid (60)
1-HO-2-naphthoic acid (60)
3-HO-2-naphthoic acid (60)
2-MeO-C6H4CO2H (60)
N-Boc-
2-F-C6H4CO2H (60)
2-HO-1-naphthoic acid (60)
2-HO-1-naphthoic acid (60)
2-HO-1-naphthoic acid (60)
62
54
99
22
63
<1
81
79
84
94
8
70
40
81
85
91
D
-Phg (40)
42
–28
n.d.
–34
–51
–44
–34
n.d.
–43
–53
–41
–51
–49
9[d]
10
11
12
13
14
15
16
17[e]
18[f]
19[g]
D
-Phg (60)
[a] Unless otherwise stated, a mixture of 2 (0.1 mmol), II (20 mol%) and co-catalyst (x mol%) in toluene (0.1
M) was stirred for 30 min, after which time
α-Angelica lactone (2 equiv.) was added and the reaction mixture left to stir for 48 h. [b] Determined by 1H NMR and GC–MS analyses of the crude product.
[c] Determined by SFC analysis of the product after column chromatography. [d] Catalyst II was omitted. [e] α-Angelica lactone (5 equiv.) added in one shot.
[f] α-Angelica lactone (3 equiv.) was added in portions over 48 h. [g] α-Angelica lactone (3 equiv.) was added in three portions over 48 h, 0.3 mmol scale for
72 h, with 77% isolated yield.
with benzene performing best (entry 8). However, for the sake Electron-poor aryl-substituted enones readily reacted at room
of using benign conditions, we chose to pursue our study with temperature to give 3d–k in high yields and enantioselectivities
the slightly inferior toluene.
but low diastereoselectivities, which could not be improved by
running the reactions at lower temperatures. In contrast, elec-
tron-rich aryl-substituted enones (giving 3l–o) displayed lower
reactivity and the reactions were performed at 40 °C. Under
these conditions, high yields and excellent enantioselectivities
were observed along with higher diastereoselectivities. Lower
diastereoselectivities were observed for heteroaromatic sub-
strates (giving 3p and 3q) and ethyl enone 2r also reacted suc-
cessfully to provide 3r, albeit with a lower yield and dia-
stereoselectivity, showing steric hindrance in the formation of
the iminium intermediate. Finally, a dienone could also be used
as substrate in this reaction, with 3s as the product.
An sp2 substituent at the γ position of the enone seems to
be necessary for the reaction to take place. Indeed, the reac-
tions of various alkyl enones (Figure 2, 2t–z) were found to be
sluggish, even at 40 °C, and only trace amounts of the products
were observed, along with recovery of the untouched starting
enone and decomposition products of the pro-nucleophile (see
The co-catalyst alone, that is, in the absence of catalyst II,
did not achieve the transformation (entry 9). We thus probed
the influence of the amount of co-catalyst used and found that
the level of conversion and diastereoselectivity plateaued with
60 mol% (entry 10). Bulkier salicylic acid analogues were tested,
and 2-hydroxy-1-naphthoic acid was found to be the best co-
catalyst in terms of diastereoselectivity (entries 11–13). Other
analogues, such as 2-methoxybenzoic acid (entry 14), gave poor
results, providing evidence that hydrogen bonding involving an
unhindered phenol plays a crucial role in activating and pre-
senting the nucleophile to the enone (see below). In addition,
the efficacy of our catalytic system was found to be superior to
that of the well-established passe-partout systems using N-Boc-
D
-phenylglycine or 2-fluorobenzoic acid as co-catalyst (en-
tries 15 and 16).[24] Finally, modifying the amounts and mode
of addition of the pro-nucleophile as well as slightly increasing
the reaction time led to the final optimised procedure.[25]
With these conditions in hand, we set out to explore the below). This contrasts with the work of Ye and Dixon, who
scope of the reaction catalysed by the combination II/2- mostly used alkyl enones as substrates with only a few exam-
hydroxy-1-naphthoic acid (Scheme 3).[26] The reaction could be ples of aryl enones. Additionally, extending the bulk on the
carried out on the gram scale, and the pseudo-enantiomeric ketone moiety to isopropyl (2aa, compared with ethyl 2r in
catalyst III allowed access to the opposite enantiomer ent-3a. Scheme 3) led to loss of reactivity. For ketones with a cyclo-
Naphthyl-substituted enones (giving 3b and 3c) provide insight alkane substituent, no reaction took place (2ab and 2ac). Fi-
into the influence of the steric hindrance on the reaction rates. nally, chalcone 2ad was also unreactive.
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As a Two-Step Procedure — Preparation of
Hexahydrobenzofuran-2(3H)-ones
With an efficient access to highly enantioenriched conjugate
adducts anti-3 as the major diastereomer in all cases, we turned
our attention to studying the cyclisation step. This transforma-
tion appeared to be unexpectedly difficult to bring about, and
various conditions were tested (Table 3). DBU (1,8-diazabi-
cyclo[5.4.0]undec-7-ene) or triethylamine were found ineffec-
tive in promoting the cyclisation (entries 1 and 2), whereas
tBuOK led to decomposition of the substrate (entry 3). Aqueous
NaOH in methanol (entry 4) led to the complete conversion of
anti-3 into 4 along with non-negligible amounts of hydrolysis
products, as did LiOH in THF (entry 5). L-Proline (entry 6) pro-
moted the desired cyclisation, but rather slowly. Not unexpect-
edly, IV promoted the cyclisation reaction (entry 7). When the
reaction was performed with rac-3 and purposely stopped at
50% conversion to measure a potential enantioenrichment in
both 3 and 4, a low 16% ee was observed for both (entry 8).
Thus, the cyclisation reaction was attempted on enantioen-
riched 3 with rac-IV; the complete conversion of anti-3 into 4
with no erosion of enantioselectivity was achieved (entry 9).
This suggests that catalyst IV is not competent for promoting
a retro-Michael addition, which would otherwise have led to
epimerisation in 3 and result in an ee value lower for 4 than for
anti-3. Catalyst II proved inefficient in promoting cyclisation
even in the presence of thiourea catalyst XIV (entries 10 and
11), benzylamine allowed cyclisation only very slowly even in
the presence of XIV (entries 12 and 13) and Takemoto catalyst
VI also failed to promote the cyclisation (entry 14), which sug-
gests that the cyclisation event takes place by enamine activa-
tion. Finally, to probe the feasibility of adding rac-IV to the
reaction mixture of the first conjugate addition in a one-pot
procedure, we used α-Angelica lactone and salicylic acid as ad-
ditives (entries 15 and 16), and found that both inhibited the
cyclisation to some extent.
With the mild conditions for the cyclisation in hand, we then
explored the scope of this reaction with a small yet representa-
tive set of substrates. As catalyst II does not promote the cycli-
sation, one may think it convenient to simply add rac-IV to
the reaction mixture after completion of the first step. This was
disproved by the observed inhibition of the cyclisation reaction
by both α-Angelica lactone and salicylic acid. Furthermore, as
complete conversion of the starting enone is not reached dur-
ing the first step while some α-Angelica lactone is still present
in the mixture, we found it easier to carry out an easy and
rapid separation of the conjugate adducts from the rest of the
components, allowing for measurement of the enantioselectiv-
ity, and then to submit them to the cyclisation conditions,
which resulted in an ee for 4 equal to that of the starting anti-
3 (Scheme 4).
Scheme 3. Scope of the Michael addition reaction.
The cyclisation reaction readily took place with all substrates,
and the cyclised products could be easily separated as single
diastereomers with excellent enantioselectivities by column
chromatography, which we found more convenient than a sim-
ple filtration of the reaction mixture despite the fact that these
compounds readily precipitate out of the reaction mixture. The
lower yield observed for 4d reflects the lower diastereomeric
Figure 2. Enones that failed to undergo conjugation addition with the present
catalytic system.
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Table 3. Study of the conditions for the cyclisation reaction.[a]
Entry
Conditions
Conv. [%][b]
anti-3 ee [%][c]
4 ee [%][c]
1
2
3
4
5
6
7
8
DBU, CH2Cl2, r.t., 24 h
Et3N, CH2Cl2, r.t., 24 h
tBuOK, THF, 0 °C, r.t.
Aq. NaOH, MeOH, r.t., 24 h
<1
<1
decomp.
hydrolysis
hydrolysis
44
–
–
–
–
–
–
–
16
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
16
99
–
–
–
–
–
–
–
LiOH, THF, r.t., 24 h
I (10 mol%), MeOH, 40 °C, 24 h
(R,R)-IV (10 mol%), PhMe, 40 °C, 24 h
(R,R)-IV (10 mol%), PhMe, 40 °C, 6 h
rac-IV (10 mol%), PhMe, 40 °C, 48 h
II (20 mol%), PhMe, 40 °C, 24 h
II + XIV (20 mol%), PhMe, 40 °C, 24 h
BnNH2 (20 mol%), PhMe, 40 °C, 24 h
BnNH2 + XIV (20 mol%), PhMe, 40 °C, 24 h
(R,R)-VI (20 mol%), PhMe, 40 °C, 24 h
rac-IV (10 mol%), PhMe, 40 °C, 48 h
rac-IV (10 mol%), PhMe, 40 °C, 48 h
91
50[d]
98 (74)
<1
9[e,f]
10
11
12
13
14
15[g]
16[h]
<1
11
31
<1
37
54
[a] Unless otherwise stated, a racemic 1:1.6 mixture of anti-3 and syn-3 was used. [b] Determined by 1H NMR and GC–MS analyses of the crude product, and
reported with respect to starting anti-3. [c] Determined by SFC analysis of the product after column chromatography. [d] A racemic 1:1.6 mixture of anti-3
and syn-3 was used and the reaction was run until 50% conversion was achieved, after which time the products were separated and analysed by SFC. [e]
Enantioenriched anti-3 (99% ee, dr 8:1) was used. [f] Isolated yield based on total 3 added as substrate is given in parentheses. [g] α-Angelica lactone (1 equiv.)
was added. [h] 2-HO-C6H4CO2H (10 mol%) was added.
ratio in the conjugate adduct 3d prior to cyclisation. Single-
crystal X-ray crystallography of 4j provided the ultimate proof
of the absolute and relative configuration (Figure 3).[27] It is in-
teresting to note that the six-membered ring is forced into an
unusual boat conformation.
Figure 3. X-ray crystal structure of 4j. Thermal ellipsoids are drawn at the 50%
probability level.
Mechanistic Aspects
From a more mechanistic point of view, three aspects relating
to the vinylogous Michael addition step remained to be ad-
dressed: the origin of the excellent enantioselectivity observed
for anti-3, the origin of syn-3 and its consistently poor enantio-
selectivity, and the fate of α-Angelica lactone during the course
Scheme 4. Representative scope of the vinylogous Michael addition/cyclisa-
tion sequence (0.5 mmol scale, yields over two steps).
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of the reaction. To gain more insight, we carried out two control
experiments (Scheme 5).
This has allowed us to propose a divergent fate for 1 in the
course of the reaction (Scheme 6). Under the reaction condi-
tions, which are mildly acidic, 1 may tautomerise to the dienol
species, which can follow three pathways. In path A, under
acidic conditions, rapid γ protonation leads to the unproductive
and irreversible formation of 5,[29] which is not able to partici-
pate in the vinylogous Michael addition reaction. Alternatively,
it can react with the enone to form either anti-3 (path B) or
syn-3 (path C). The outcome of this reaction is due to a very
fine balance between these three processes.
Scheme 5. a) Stoichiometric experiment, b) reaction with benzhydrylamine
or benzylamine as catalyst and c) reaction with regioisomer 5 as pro-nucleo-
phile.
Scheme 6. Proposed fate of α-Angelica lactone 1 and origin of the formation
of anti-3 and syn-3.
In a stoichiometric experiment (Scheme 5, a), pre-formation
of the iminium species led to a greatly accelerated reaction,
which was complete within a few hours, and a sensibly higher
According to numerous other reports cited herein, the for-
diastereoselectivity. This confirms that conjugate adduct anti-3 mation of syn-3 is kinetically favoured owing to a steric prefer-
is obtained by conjugate addition to the enone activated as its ence for Si-face approach of the butenolide on the enone/enal.
iminium counterpart, and that syn-3 is formed by a different The absence of reactivity with salicylic acid alone and the virtu-
activation mode, perhaps by Brønsted acid activation by an ally perfect enantioselectivity for anti-3 and moderate enantio-
ammonium species derived from II, very much in analogy to selectivity for syn-3 suggest that the catalyst is involved in both
the work of Lin and co-workers.[17]
processes.
Benzhydrylamine clearly lacks the quinuclidine moiety,
However, as iminium activation solely leads to the formation
which, with the participation of the acid co-catalyst in a tight of the anti product (see above and below), a different mode of
ion pair, is known to block one face of the iminium species, but activation must operate for the formation of syn-3; we believe
we felt it was inconsequential for a racemic experiment. It may, that Brønsted acid activation takes place, very much in agree-
however, be regarded as sterically equivalent to catalyst II, but ment with the work of Lin and co-workers.[17,30] Under our reac-
lacking the quinoline nitrogen. When benzhydrylamine was tion conditions, the excess of acid co-catalyst and the difference
used as catalyst (Scheme 5, b), low reactivity with selectivity in pKa suggest that the quinuclidine and the primary amine,
towards the formation of syn-3 was observed.[28] This suggests when not engaged in iminium formation, are both fully proto-
the interaction of the nitrogen in the quinoline moiety with a nated. The corresponding bis-ammonium species may in turn
molecule of co-catalyst, thereby explaining the improvements behave like a Brønsted acid, in analogy with thiourea catalysts,
observed with up to 3 equivalents of co-catalyst per catalyst activating the enone or the pro-nucleophile or both. This non-
molecule, and the fact that this improvement plateaued beyond covalent mode of activation is normally faster than the covalent
this value. This does not remove the steric factor from the equa- iminium activation. With no change observed in diastereomeric
tion, as benzylamine, which is electronically equivalent to benz- ratios on longer exposure under the reaction conditions, both
hydrylamine, performed poorly as a catalyst for the transforma- processes are irreversible under acidic conditions.
tion.
Finally, in the experiment with
This suggests that the catalytic system not only accelerates
as pro-nucleophile iminium formation but also over-rides the steric preferences in
5
(Scheme 5, c), only trace amounts of anti-3 were obtained, the approach of the nucleophile towards the electrophile. This
which suggests that the non-productive isomerisation of 1 to 5 effect may be due to the unique architecture of the catalytic
by protonation of the dienol species, the actual nucleophile for system involving the quinoline moiety in catalyst II on the one
the vinylogous Michael addition, leads to loss of the nucleo- hand, but also, and especially, the appending phenolic groups
phile, thereby explaining the need for the portionwise addition in the co-catalyst, thereby allowing it to out-compete the Brøn-
of 1 over an extended period of time.
sted acid activation.
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Our various observations have allowed us to propose a tran- philicity of the butenolide by hydrogen bonding to the carb-
sition state (Figure 4). The orientation of the iminium ion is well onyl. The absence of reactivity with tertiary amine-thiourea cat-
established and documented.[31] So is the high selectivity for alyst VI suggests that the substrate cyclises under enamine acti-
the attack on the Re face of the enone, due to efficient shielding vation by a primary amine. Catalyst IV is less bulky than II,
of the Si face by a molecule of acid co-catalyst forming a tight which perhaps prevents access to a conformation allowing for
ion-pair with the quinuclidine moiety in apolar solvents. This cyclisation. Thus, even if the enamine may be formed, this may
was confirmed by the reversed high enantioselectivity observed explain the absence of cyclisation when II was used as catalyst,
in DMSO, which breaks ion pairs and exposes the quinuclidin- even in the presence of a thiourea.
ium moiety promoting the approach of the nucleophile from
the Si face. A second molecule of the acid co-catalyst then pro-
tonates the imine to the activated iminium species, and its ap-
pending phenol may play the role of an activating and directing
group for the incoming pro-nucleophile through hydrogen
bonding. The proton transfer involved in the activation of the
nucleophile may, however, be slow and a third molecule of co-
catalyst could bridge the quinoline moiety to promote the de-
protonation of the pro-nucleophile. This last event, along with
the steric clash between the methyl group in 1 and the quinol-
ine moiety in the catalyst, may be responsible for the high face
selectivity in the approach of the nucleophile.[32] A priori en-
tropically costly, this self-assembled dynamic hydrogen-bond-
ing network may explain the robustness of this catalyst system
towards higher temperatures.[33]
Figure 5. Proposed rationale for the selective cyclisation of anti-3 (only the
enamine activation is represented for clarity).
Although cyclisation product 4 presents an a priori rather
unfavourable boat conformation, the cyclisation of anti-3 may
proceed through a lower-energy chair conformation in which
the phenyl substituent is equatorial. In contrast, in order to
cyclise, syn-3 would require this phenyl substituent to be axial,
leading to steric hindrance with the nearby γ-methyl and ꢀ-
hydrogen of the butenolide. This forces rotation, which may
minimise the energy of the system, but also places the reactive
moieties far apart thereby preventing cyclisation.
Conclusion
We have developed an efficient protocol for the divergent ac-
cess to γ,γ-disubstituted butenolides and hexahydrobenzo-
furan-2(3H)-ones, and we believe that these transformations will
find applications in the total synthesis of natural products and
other medicinally relevant compounds. Indeed, the inability of
the catalyst to promote the cyclisation was turned to our ad-
vantage to access both the conjugate adducts in generally high
yields, excellent enantioselectivities and modest-to-excellent
diastereoselectivities and the bicyclic structures in a subsequent
step in a highly diastereoselective manner. The protocol is oper-
ationally easy and the conjugate addition is achieved from
readily available starting materials, catalyst and co-catalyst un-
der mild reaction conditions. This new self-assembled catalytic
system has also demonstrated its robustness and out-per-
formed already established systems and will certainly find appli-
cations in other difficult reactions involving Michael additions
to enones under iminium activation. In addition, a broad range
of aryl- and heteroaryl-substituted enones could be used as
substrate for the vinylogous Michael addition. Extension of the
Figure 4. Proposed transition state for the formation of anti-3.
Finally, the high selectivity observed for the cyclisation of scope of this reaction to aliphatic enones proved, however, to
only diastereomer anti-3 under the reaction conditions may be be difficult due to their lower reactivity. The contribution by Ye
solely due to conformational restrictions (Figure 5). The thiourea and Dixon, however, may well plug into this work to access
moiety may play an important role in enhancing the electro- further diversity in the preparation of synthetically relevant
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[4]
S. P. Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am. Chem. Soc. 2003,
125, 1192–1194.
A. Quintard, A. Lefranc, A. Alexakis, Org. Lett. 2011, 13, 1540–1543.
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hexahydrobenzofuran-2(3H)-ones and for their application as
synthons in natural product synthesis.
[5]
[6]
[7]
Reaxys search for natural products consisting of variably substituted and
unsaturated 7a-methylhexahydrobenzofuran-2(3H)-ones and structurally
related lactols, acetals, dihydro- and tetrahydrofuran derivatives, March
2015.
Experimental Section
Representative Procedure for the Vinylogous Michael Addition
Reaction: A solution of 9-amino-9-deoxy-epi-quinine (II; 0.02 mmol)
[8]
[9]
in toluene (1 mL, 0.1
M
) was added to a 5-mL vial equipped with a
a) H.-L. Cui, J.-R. Huang, J. Lei, Z.-F. Wang, S. Chen, L. Wu, Y.-C. Chen, Org.
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magnetic stirring bar and charged with 2-hydroxy-1-naphthoic acid
(0.06 mmol, 60 mol%). After stirring at room temperature for
10 min, all the acid had dissolved and enone 2 (0.1 mmol, 1 equiv.)
was added to the yellow solution. After stirring at the same temper-
ature for 10 min, α-Angelica lactone (0.1 mmol, 1 equiv.) was added
dropwise, neat or as a solution in toluene (typically 100 μL), and
the reaction was stirred at the same temperature. Further portions
of α-Angelica lactone (0.1 mmol, 1 equiv.) were added at 24 h and
48 h. After 72 h, the reaction mixture was diluted with EtOAc,
washed successively with water, saturated aqueous NaHCO3 and
brine, dried with Na2SO4, filtered and concentrated under reduced
pressure. The diastereomeric ratio was measured by 1H NMR and
GC–MS analyses. The residue was dry-loaded and purified by flash
column chromatography on silica gel using cyclohexane/EtOAc
(10:1 to 2:1) as eluent to afford, upon evaporation, the desired con-
jugate adduct 3. SFC analysis using the stated column and elution
conditions provided the enantiomeric excess.
For Dukunolides D–F, see: a) M. Nishizawa, Y. Nademoto, S. Sastrapradja,
M. Shiro, Y. Hayashi, J. Chem. Soc., Chem. Commun. 1985, 395–396; b) M.
Nishizawa, Y. Nademoto, S. Sastrapradja, M. Shiro, Y. Hayashi, Phytochem-
istry 1988, 27, 237–239; c) N. Saewan, J. D. Sutherland, K. Chantra-
promma, Phytochemistry 2006, 67, 2288–2293; for Granatoine, see: d) J.
Cui, J. Ouyang, Z. Deng, W. Lin, Magn. Reson. Chem. 2008, 46, 894–897;
for Xylogranatins F and H, see: e) J. Wu, S. Zhang, T. Bruhn, Q. Xiao, H.
Ding, G. Bringmann, Chem. Eur. J. 2008, 14, 1129–1144; for Hainangrana-
tumin G, see: f) J.-Y. Pan, S.-L. Chen, M.-Y. Li, J. Li, M.-H. Yang, J. Wu, J.
Nat. Prod. 2010, 73, 1672–1679; for Acremolactone A, see: g) T. Sassa, H.
Kinoshita, M. Nukina, T. Sugiyama, J. Antibiot. 1998, 51, 967–969.
For a full report on Cneorins and structurally related natural products,
see: a) A. Mondon, B. Epe, H. Callsen, Liebigs Ann. Chem. 1983, 1760–
1797; b) A. Mondon, D. Trautmann, U. Oelbermann, B. Epe, Liebigs Ann.
Chem. 1983, 1798–1806, and references cited therein.
For an example of a Michael/Michael(/retro-Michael) sequence, see: J.-
W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C. Chen, Y. Wu, J. Zhu,
J.-G. Deng, Angew. Chem. Int. Ed. 2007, 46, 389; Angew. Chem. 2007, 119,
393–392. The full sequence could not be achieved cleanly with 9-amino-
9-deoxy-epi-quinine only, but subsequent cyclisation with benzylammo-
nium trifluoroacetate allowed for clean cyclisation in a subsequent step.
For examples of Michael/aldol sequences with a pyrazolidine derivative
as catalyst, see: a) N. Halland, P. S. Aburel, K. A. Jørgensen, Angew. Chem.
Int. Ed. 2004, 43, 1272; Angew. Chem. 2004, 116, 1292–1277; b) J. Pulk-
kinen, P. S. Aburel, N. Halland, K. A. Jørgensen, Adv. Synth. Catal. 2004,
[10]
[11]
Representative Procedure for the Cyclisation: The catalyst rac-IV
(0.01 mmol, 10 mol%) was added to a 5-mL vial equipped with a
magnetic stirring bar and charged with a solution of conjugate ad-
duct 3 (0.1 mmol) in toluene (1 mL). The resulting reaction mixture
was stirred at 40 °C for 48 h. The mixture was diluted with EtOAc,
successively washed with water and brine, dried with Na2SO4, fil-
tered and concentrated under reduced pressure. The residue was
dry-loaded and purified by flash column chromatography on silica
gel using cyclohexane/EtOAc (10:1 to 1:1) as eluent to afford, upon
evaporation, the desired bicyclic compound 4.
[12]
346, 1077–1080; for an example with L-Proline as catalyst, see: c) D.
Gryko, Tetrahedron: Asymmetry 2005, 16, 1377–1383.
[13]
[14]
For examples of Michael/Mannich sequences with 9-amino-9-deoxy-epi-
quinine as catalyst, see: a) Q. Cai, C. Zheng, J.-W. Zhang, S.-L. You, Angew.
Chem. Int. Ed. 2011, 50, 8665; Angew. Chem. 2011, 123, 8824–8669; b) Q.
Cai, S.-L. You, Org. Lett. 2012, 14, 3040–3043.
W. Zhang, D. Tan, R. Lee, G. Tong, W. Chen, B. Qi, K.-W. Huang, C.-H. Tan,
Z. Jiang, Angew. Chem. Int. Ed. 2012, 51, 10069; Angew. Chem. 2012, 124,
10216–10073.
D. Yang, L. Wang, D. Zhao, F. Han, B. Zhang, R. Wang, Chem. Eur. J. 2013,
19, 4691–4694.
J. Ji, L. Lin, L. Zhou, Y. Zhang, Y. Liu, X. Liu, X. Feng, Adv. Synth. Catal.
2013, 355, 2764–2768.
Acknowledgments
The authors thank the Swiss National Research Foundation
(grant number 200020-126663) and the COST action CM0905
(SER contract number C11.0108) for financial support.
[15]
[16]
Keywords: Organocatalysis · Asymmetric synthesis ·
Enantioselectivity · Michael addition · Lactones
[17]
[18]
U. Das, Y.-R. Chen, Y.-L. Tsai, W. Lin, Chem. Eur. J. 2013, 19, 7713–7717.
L. Yin, H. Takada, S. Lin, N. Kumagai, M. Shibasaki, Angew. Chem. Int. Ed.
2014, 53, 5327; Angew. Chem. 2014, 126, 5431–5331.
[19]
[20]
[21]
Most of the results from this work were presented at the 6th ORCA
meeting (COST action CM0905), Palermo, 8 May 2014: R. Lagoutte, A.
Alexakis, Organocatalysed Direct Double Michael Addition of Unactivated
α-Angelica Lactone to Enones.
X. Li, M. Lu, Y. Dong, W. Wu, Q. Qian, J. Ye, D. J. Dixon, Nature Commun.
2014, 5, 4479. The protocol uses a mono-tosylated diphenylethylene
[1] For selected reviews on organocatalysed cascade reactions, see: a) D.
Enders, C. Grondal, M. R. M. Hüttl, Angew. Chem. Int. Ed. 2007, 46, 1570;
Angew. Chem. 2007, 119, 1590–1581; b) A. Erkkilä, I. Majander, P. M.
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Chem. 2008, 6, 2037–2046; d) A.-N. Alba, X. Companyo, M. Viciano, R.
Rios, Curr. Org. Chem. 2009, 13, 1432–1474; e) C. Grondal, M. Jeanty, D.
Enders, Nature Chem. 2010, 2, 167–178; f) B. Westermann, M. Ayaz, S. S.
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858–849; g) C. M. R. Volla, I. Atodiresei, M. Rueping, Chem. Rev. 2014,
114, 2390–2431; for books on the the subject, see: h) P.-F. Xu, J.-B. Ling,
Catalytic Cascade Reactions (Eds.: P.-F. Xu, W. Wang), Wiley-VCH, Wein-
heim, Germany, 2014, p. 123–144.
diamine-derived L-tert-leucine-based primary amine catalyst in conjunc-
tion with o-nitrobenzoic acid as co-catalyst in CH2Cl2.
The relative absolute configurations were determined by the preparation
of 3 by an alternative route consisting of a conjugate addition according
to ref.[5], treatment of the resulting aldehydes with MeMgBr and DMP
oxidation of the resulting diastereomeric mixture of secondary alcohols,
followed by assignment by 1H NMR, GC–MS and SFC analyses (see
Schemes S-2.1 and S-2.2, in: the Supporting Information for details).
When a racemic 1:1.6 mixture of anti-3 and syn-3 was treated with rac-
IV, an enriched 1:4.2 mixture was obtained along with 4 (26% conver-
[2] M. Seitz, O. Reiser, Curr. Opin. Chem. Biol. 2002, 6, 453–458.
[3] For reviews, see: a) Q. Zhang, X. Liu, X. Feng, Curr. Org. Synth. 2013, 10,
764–785; b) C. Schneider, F. Abels, Org. Biomol. Chem. 2014, 12, 3531–
3543.
[22]
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sion, 65% based on anti-3; see Scheme S-2.3 in the Supporting Informa-
tion for details).
and a pseudo-racemic mixture of II and III was found unsatisfactory
owing to the difference in reactivity of the two catalysts.
[23] Attempts to optimise the reaction conditions with catalysts IV or V with
the aim of steering the diastereoselectivity towards anti-3 and improving
the enantioselectivity failed in our hands. Indeed, a range of solvents
and co-catalysts were screened, and the initial conditions were found to
give the “best” results (see Tables S-3.2–S-3.5 in the Supporting Informa-
tion for details).
[29] Y. Wu, R. P. Singh, L. Deng, J. Am. Chem. Soc. 2011, 133, 12458–12461.
[30] This does not mean that syn-3 is always preferentially formed by Brøn-
sted acid activation. In fact, when a mixture of 1 and 2 was treated with
catalyst VI instead of IV under otherwise identical conditions, no reac-
tion took place, thereby confirming that IV may activate the enone as
the iminium species.
[24] For a review, see: P. Melchiorre, Angew. Chem. Int. Ed. 2012, 51, 9748;
Angew. Chem. 2012, 124, 9886–9770.
[31] A. Moran, A. Hamilton, C. Bo, P. Melchiorre, J. Am. Chem. Soc. 2013, 135,
9091–9098.
[25] Concentrations, catalyst loading, temperature and additives were also
screened. See Tables S-3.6 and S-4.1–S-4.7 in the Supporting Information
for the full set of conditions screened.
[26] All the starting enones were obtained in good yields from the corre-
sponding commercially available aldehydes by aldol condensation/elimi-
nation, Wittig olefination or by a two-step Grignard addition/MnO2 oxid-
ation sequence.
[27] CCDC 1433562 (for 4j) contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre.
[32] The proposed transition state shows a really good match for a Diels–
Alder reaction with an endo transition state stabilised by secondary or-
bital overlap. Thus, an alternative pathway involving a Diels–Alder cyclo-
addition/ring opening sequence cannot be ruled out. We have, however,
never observed any intermediate pointing towards that possibility.
[33] When 2a was treated with 1 and in the presence of the optimised cata-
lytic system at 70 °C, anti-3a was obtained with over 99% ee, albeit
with moderate conversion and lower diastereoselectivity due to other
competing pathways.
[28] Benzhydrylamine was used for the preparation of racemates and consist-
ently provided diastereomeric ratios in favour of syn-3. Other systems
were probed, but with benzylamine the reaction proceeded too poorly,
Received: June 9, 2016
Published Online: ■
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Aminocatalysis
An efficient protocol for the divergent
access to γ,γ-disubstituted butenolides
and hexahydrobenzofuran-2(3H)-ones
is described. The two steps are run un-
der very mild conditions and use read-
ily available catalysts and co-catalysts.
A new co-catalyst class is described for
the first step.
R. Lagoutte, C. Besnard,
A. Alexakis* ....................................... 1–11
Direct Organocatalysed Double
Michael Addition of α-Angelica Lact-
one to Enones
DOI: 10.1002/ejoc.201600707
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