Multicatalytic, asymmetric Michael/Stetter reaction of salicylaldehydes and activated alkynes

Article abstract of DOI:10.1073/pnas.1002830107

Wereport the development of a multicatalytic, one-pot, asymmetric Michael/Stetter reaction between salicylaldehydes and electrondeficient alkynes. The cascade proceeds via amine-mediated Michael addition followed by an N-heterocyclic carbene-promoted intr

Full text of DOI:10.1073/pnas.1002830107

Multicatalytic, asymmetric Michael/Stetter reaction
of salicylaldehydes and activated alkynes
Claire M. Filloux, Stephen P. Lathrop, and Tomislav Rovis1
Department of Chemistry, Colorado State University, Fort Collins, CO 80523
Edited by David W. C. MacMillan, Princeton University, Princeton, NJ, and accepted by the Editorial Board May 30, 2010 (received for review March 22, 2010)
Wereport the development of a multicatalytic, one-pot, asymmetric
Michael/Stetter reaction between salicylaldehydes and electron-
Ar
Ar
N
H
3
OTMS
O
O
deficient alkynes. The cascade proceeds via amine-mediated
Michael addition followed by an N-heterocyclic carbene-promoted
intramolecular Stetter reaction. A variety of salicylaldehydes, dou-
bly activated alkynes, and terminal, electrophilic allenes participate
in a one-step or two-step protocol to give a variety of benzofura-
none products in moderate to good yields and good to excellent
enantioselectivities. The origin of enantioselectivity in the reaction
is also explored; E∕Z geometry of the reaction intermediate as
well as the presence of catalytic amounts of catechol additive are
found to influence reaction enantioselectivity.
HO Me
(20 mol %)
Me
O
Me
Me
Me
Ar = 3,5-(CF3)2C6H3
1
O
+
O
BF4
N
Me
5
2
N
N
C6F5
(10 mol %)
NaOAc (10 mol %)
4a
Two-Pot
46% yield
5:1 dr
One-Pot
93% yield
85:15:<1:<1 dr
86% ee
58% ee
CHCl3, 23
C
O
O
Me
*
O
Me
catalysis ∣ organic synthesis ∣ tandem catalysis
Me
6
Scheme 1. Multicatalytic Michael/Benzoin cascade.
ascade catalysis has garnered significant recent attention
from the synthetic community as a means to swiftly assemble
C
complex molecules from simple starting materials with minimal
time, waste, and manipulation of reaction intermediates (1–11).
Especially powerful in its application to total synthesis, asym-
metric tandem catalysis has enabled rapid access to enantioen-
riched products with high levels of selectivity (1, 4–8, 10, 11).
Although most examples exploit a single catalyst to promote mul-
tiple, sequential transformations (12–19), systems relying on two
or more catalysts have been reported (2, 3, 11, 20). Inherent in
any multiple catalyst system is the challenge of compatibility.
Avoidance of mutual interference often obliges stepwise addition
of catalysts or reagents and variation of reaction conditions over
time (21–26). Nevertheless, cascades triggered by a single opera-
tion have been accomplished (20, 27, 28).
benzofuranones. In 2008, Jørgensen and coworkers reported
that 2-tert-butoxy carbonyl benzofuranone could be alkylated
asymmetrically with tetraethyl ethylidene-bisphosphonate to give
the corresponding 2,2′-disubstituted product in excellent enan-
tioselectivity (44). In a different approach, we have shown that
chiral triazolinylidene carbenes mediate the cyclization of
aldehyde-tethered, β,β-disubstituted Michael acceptors related
to 12 to give benzofuranone products in excellent enantioselectiv-
ities (Scheme 2) (45–47).
Although the strategies described provide benzofuranone pro-
ducts in good yield and exceptional selectivities, both make use of
substrates that require multiple steps to prepare (47). We ima-
gined that we could expedite the synthesis of benzofuranone
products 9 by assembling intermediate aldehydes 12 in situ via
a base-catalyzed conjugate addition reaction of salicylaldehydes
7 and electrophilic alkynes 8 (Scheme 2). Fan et al. have shown
that 1,4-diazabicyclo[2.2.2]octane (DABCO) (10) efficiently med-
iates the addition of amine and oxygen nucleophiles to dimethyl
acetylenedicarboxylate (DMAD) (8a) and alkyl propiolates
(48, 49). In our envisioned sequence, a tertiary amine such as
quinuclidine (11) or DABCO (10) activates alkyne 8 toward
nucleophilic attack to give intermediate aldehyde 12 (Scheme 2).
Subsequent chiral carbene-promoted Stetter reaction sets a
quaternary stereocenter and yields product 9 asymmetrically.
Crucial to the success of any catalytic cascade is a compatible
catalyst system. For many Stetter systems, tertiary amines per-
form as optimal bases for carbene generation (47, 50, 51). For
Very recently, we reported the development of a one-step,
asymmetric Michael/benzoin reaction of β-ketoesters 1 and α,β-
unsaturated aldehydes 2 mediated by compatible amine 3 and
N-heterocyclic carbene (NHC) catalysts (Scheme 1) (29). Impor-
tantly, the one-pot procedure was found to give elaborated cyclo-
pentanone products 5 in higher yield and enantioselectivity than a
stepwise protocol, wherein intermediate aldehyde 6 is isolated and
subjected to the benzoin reaction in a subsequent step (Scheme 1).
This observation testifies to the power of cascade catalysis: By
quickly relaying intermediates from one reaction to the next, cat-
alysts can work synergistically to discourage undesired pathways.
Encouraged by the discovery that NHCs could participate in
cascade catalysis, we were inspired to use NHCs to mediate the
cascade assembly of benzofuranone products 9 asymmetrically
(30). A range of biological activities associated with 3(2H)-benzo-
furanones including antifungal (31, 32), antipsychotic (33), and
anticancer (34–36) properties make these products attractive
synthetic targets. Among natural products containing a 2,2′-disub-
stituted benzofuranone core, rocaglamide demonstrates appreci-
able cytotoxicity in mice and human cells lines (37), vinigrol
displays antihypertensive properties (38), and Sch202596 shows
promise in Alzheimer’s therapy (39).
Author contributions: T.R. designed research; C.M.F. and S.P.L. performed research; and
C.M.F., S.P.L. and T.R. wrote the paper.
The authors declare no conflict of interest.
This article is
a PNAS Direct Submission. D.W.M. is a guest editor invited by the
Editorial Board.
Data deposition: The coordinates for the crystal structure of 9da have been deposited in
the Cambridge Structural Database, Cambridge Crystallographic Data Centre, www.ccdc
.cam.ac.uk/products/csd/, Cambridge CB2 1EZ, United Kingdom (CSD reference no. CCDC
783384).
Although a number of methods for the racemic assembly of
benzofuranones containing C2 quaternary centers have been re-
ported, many proceed from relatively advanced starting materials
(40, 41) or suffer from competitive reaction pathways (42, 43).
More rare are enantioselective preparations of 2,2′-disubstituted
1To whom correspondence should be addressed. E-mail: rovis@lamar.colostate.edu.
This article contains supporting information online at www.pnas.org/lookup/suppl/
doi:10.1073/pnas.1002830107/-/DCSupplemental.
20666–20671 ∣ PNAS ∣ November 30, 2010 ∣ vol. 107 ∣ no. 48
www.pnas.org/cgi/doi/10.1073/pnas.1002830107

N
N
Table 1. Solvent and temperature screen
O
EWG
O
10
11
or
O
CO2Me
O
O
EWG
EWG
N
CO2Me
CO2Me
1)
(20 mol %)
11
O
O
N
OH EWG
N
7
8
9
OH CO2Me
solvent (0.1 M), T1
N
7a
8a
12aa
N
4b BF4
Ar
O
N
EWG
EWG
I
N
N
O
NR3
BF4
2) (20 mol %)
CO2Me
CO2Me
C6F5
4b
O
O
R
N
N
solvent (0.1 M), T2
9aa
N
Ar
O
Entry
Solvent
T1, °C T2, °C Yield, % ee, %
EWG
OH
EWG
1
2
3
4
5
6
7
8
9
CH2CI2
THF
t-amyl alcohol
23
23
0
0
85
76
63
87
82
75
60
64
NR
81
83
78
86
89
86
90
92
NA
O
EWG
O
12
II
EWG
23
0
PhMe/t-amyl alcohol (9∶1)
23
0
Scheme 2. Envisioned multicatalytic Michael/Stetter cascade.
PhMe
PhMe
PhMe
PhMe
PhMe
23
0
23
23
23
−40
23
−10
−40
NA
this reason, we were encouraged that DABCO or quinuclidine
would not only serve as nucleophilic “triggers” (48) to promote
our imagined conjugate addition reaction but would also prove
suitable bases to deprotonate triazolium salt precatalyst 4b and
generate the active carbene species.
NA, not applicable; NR, no reaction.
alternative pathway could be imagined in which quinuclidine
deprotonates salicylaldehyde, which adds conjugately to DMAD.
To examine the viability of a base-catalyzed pathway, we ex-
changed quinuclidine for diisopropylethylamine. Treatment of
salicylaldehyde and DMAD with this less competent nucleophile
but similarly strong base resulted in complete recovery of
starting material, suggesting that the proposed nucleophilic
pathway is likely at work in our developed conditions (Eq. 2).
Moreover, exposure of salicylaldehyde and DMAD to the free
carbene derived from azolium salt 4b gave no observable product
by 1H NMR spectroscopy (Eq. 3). It is highly probable that
quinuclidine (11) rather than carbene-4b participates as the
nucleophilic activator in our system.
Results and Discussion
We first examined whether our envisioned cascade could be per-
formed in a one-pot, stepwise fashion. Carbenes have been shown
capable of nucleophilic addition into DMAD and other activated
alkynes (52, 53). To circumvent this undesired reaction pathway, a
mixture of salicylaldehyde (7a) and DMAD (8a) was treated
first with quinuclidine 11 and then with triazolium salt 4b. Ben-
zofuranone product 9aa was isolated from this one-pot, two-step
sequence in good overall yield and enantioselectivity (Table 1,
entry 1). In a brief solvent screen, dichloromethane and 9∶1
toluene/t-amyl alcohol provided product 9aa in similarly high
yields (Table 1, entries 1 and 4), whereas toluene gave the highest
level of enantioselectivity (Table 1, entries 1–5). Lowering tem-
peratures of the Stetter reaction improves enantioselectivity
slightly but results in longer reaction times and lower product
yields (Table 1, entries 6–8). No productive reaction is observed
when the conjugate addition reaction is conducted at low tem-
peratures (Table 1, entry 9).
O
CO2Me
O
DIPEA (20 mol %)
PhMe, 23 C
CO2Me
CO2Me
[2]
OH CO2Me
O
7a
8a
12aa
O
Although we had developed conditions to mediate two bond-
forming events in one reaction vessel with high levels of asym-
metric induction, we hoped to reduce the number of required
synthetic manipulations to a single operation. To this end, we
treated a mixture of 7a, 8a, and 4b with quinuclidine (11) at 0
°C in toluene. To our delight, the cascade proceeds smoothly
to give 9aa in undiminished yield and enantioselectivity
(Eq. 1). The one-step protocol was found to be scalable: On a
1 g scale, product 9aa (1.48 g, 79% yield) is obtained in 88% en-
antiomeric excess (ee). When the one-step reaction is performed
in dichloromethane, however, only starting material and decom-
position products are recovered; under these conditions, nucleo-
philic addition of 4b-derived carbene into DMAD may interfere
with the desired conjugate addition reaction (Eq. 1).
N
N
N
Ar
O
O
CO2Me
[3]
carbene-4b
PhMe, 23
CO2Me
CO2Me
C
O
OH CO2Me
7a
8a
12aa
With a productive one-step protocol in hand, we investigated
the scope of the reaction with respect to salicylaldehyde 7. Indeed,
both electron-rich and electron-deficient salicylaldehydes with
various substitution patterns participate in the Michael/Stetter se-
quence to give products 9 in good yields and moderate to excellent
enantioselectivites (Table 2). Electron-deficient salicylaldehydes
give generally higher enantioselectivities but poorer yields than
electron-rich salicylaldehydes. The lower yields observed for these
substrates are attributed to the competitive formation of chro-
mene side products 13 derived from intramolecular aldol of inter-
mediate enolate III (Eq. 4). Ortho-substituted salicylaldehydes
give the lowest observed yields; steric bulk surrounding the phen-
oxide apparently impedes nucleophilic addition into DMAD
(Table 2, entries 9–10). Indeed, when the 3-substituent is suffi-
ciently large, no conjugate addition is observed (Table 2, entry 10).
Absolute configuration of products 9 was assigned by X-ray crystal
structure of iodide 9da. The others were assigned by anology.
O
O
CO2Me
4b (20 mol %)
11 (20 mol %)
CO2Me
CO2Me
O
OH CO2Me
PhMe, 0
C
[1]
9aa
7a
8a
PhMe: 78% yield
89% ee
CH2Cl2: no reaction
A series of control experiments were performed to probe
the mechanism of the conjugate addition reaction. We had
envisioned that Michael addition proceeds through nucleophilic
activation of DMAD via intermediate I (Scheme 2). However, an
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O
O
O
We were intrigued by the variation of enantioselectivity across
products 9 which appeared to be independent of steric or electro-
nic factors. For example, 4- and 5-methoxy substrates 7h and 7g
afford identical ees in spite of their differing electronic impact
on both aldehyde and tethered alkene (Table 2, entry 7 vs. 8).
Furthermore, sterically similar substrates 7d and 7e give products
with widely disparate ees (Table 2, entry 4 vs. 5, 94% and 86% ee,
respectively, corresponding to ∼0.5 kcal∕mol energy difference).
To probe the origin of ee variation, we performed a two-pot
Michael/Stetter protocol wherein intermediate aldehyde 12 was
isolated and subjected to Stetter conditions. Treatment of DMAD
and salicylaldehydes 7f, 7a, and 7c with base gives the correspond-
ing intermediate aldehydes 12fa, 12aa, and 12ca in good yields
(Scheme 3). When intermediate aldehydes 12fa, 12aa, and 12ca
are exposed to precatalyst 4b and base in the usual manner, how-
ever, products 9fa, 9aa, and 9ca are obtained in appreciably lower
and more uniform enantioselectivities than those observed in the
one-pot procedure (Scheme 3). We speculated that a trace impur-
ity present in or side-product derived from certain salicylaldehydes
7 might be crucial for the high enantioselectivities obtained in the
one-pot protocol; removal of the species during isolation of inter-
mediate 12 would result in a drop in enantioselectivity of the
subsequent Stetter reaction. Indeed, when the Stetter reactions
of intermediate aldehydes 12ca and 12fa are conducted in the
presence of an equivalent of exogenous salicylaldehyde 7c, the
high enantioselectivities of products 9ca and 9fa are recovered
(Table 3, entries 1 and 2).
OH
O
CO2Me
CO2Me
OMe
CO2Me
Aldol
[4]
- 11
N
III
13
Table 2. Salicylaldehyde scope
O
CO2Me
O
4b (20 mol %)
base (20 mol %)
CO2Me
CO2Me
R
R
Entry
1
O
OH CO2Me
PhMe, 0
C
7
8a
9
7
Base
11
Product (9)
Yield, %
ee, %
89
O
CO2Me
CO2Me
7a
7b
78
65
O
aa
O
Cl
CO2Me
2
10
89
O
CO2Me
ba
We aimed to identify the species present in exogenous salicy-
laldehydes 7 that might promote elevation of enantioselectivity.
Strong H-bond donors such as catechols have been shown to
improve yields and enantioselectivities of enamine-promoted
Michael additions of aldehydes into enones (54–56). We hypothe-
sized that trace catechol derived from Dakin-oxidation (57, 58)
of salicylaldehyde might contribute to Stetter enantioselectivity.
Addition of 10 mol % catechol 14a to the Stetter reaction of
intermediate aldehydes 12ca and 12fa improved product enan-
tioselectivities to excellent 94% ee and 92% ee, respectively
(Table 3, entries 3 and 4). When catechol 14a is added with
precatalyst 4b in the one-pot, two-step protocol, similar improve-
ment in enantioselectivity is observed for a variety of substrates
O
Br
CO2Me
CO2Me
3
4
7c
10
11
64
94
O
ca
O
I
CO2Me
CO2Me
7d
68
77
80
66
68
94
86
85
86
85
O
da
O
Me
CO2Me
CO2Me
5
6
7
8
7e
7f
11
11
10
11
O
ea
ga
O
t-Bu
CO2Me
CO2Me
O
O
MeO
MeO
CO2Me
CO2Me
7g
7h
O
ha
ia
O
CO2Me
CO2Me
O
O
CO2Me
CO2Me
9
7i
7j
10
11
62*
NR
92
O
ja
MeO
t-Bu
O
CO2Me
CO2Me
10
NA
O
ha
Br
NA, not applicable; NR, no reaction.
*9ja could not be separated from a minor impurity which coeluted in a
variety of solvent systems.
Scheme 3. Two-pot Michael/Stetter reaction.
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Filloux et al.

Table 3. Additive effect on Stetter enantioselectivity
somer 15ad is obtained in high enantioselectivity (89%) relative to
major product 9ad (Table 5, entry 3). Phosphonate ester 8e reacts
in the one-pot, two-step protocol to give phosphonate 9ae in fair
yield and good enantioselectivity (Table 5, entry 4).
Although we were pleased to find that a number of unsymme-
trical alkynes were tolerated in our one-pot protocol, we were
interested in identifying substrates that would participate with
high levels of both regioselectivity and enantioselectivity. Inter-
mediate aldehydes 16a containing a single electron-withdrawing
substituent on the Michael acceptor have been shown to undergo
the Stetter reaction with high enantioselectivity under conditions
similar to these (Eq. 5) (47). Our initial attempt to access related
intermediate aldehyde 16b via the necessarily regioselective Mi-
chael addition of salicylaldehyde (7a) into alkynoate 17 resulted
4b (20 mol %)
base (20 mol %)
additive (equiv)
O
O
CO2Me
CO2Me
CO2Me
CO2Me
R
R
O
PhMe, 0
C
O
12
9
ee, %
Entry 12 Base Additive Equiv Yield, % W/o additive W/additive
1
2
3
4
12ca 10
12fa 11
12ca 10
12fa 11
7c
7c
14a
14a
1.05
1.05
0.1
78
63
90
84
86
83
86
83
93
89
94
92
0.1
EtO2C
OH
OH
=
14a
Table 5. Unsymmetrical alkyne scope
(Table 4, entries 1–3). Little change in selectivity is experienced in
the one-pot, one-step procedure. Presumably, catechol 14a adds
conjugately to DMAD (8a) (48). Finally, an observed match/
mismatch effect provides convincing support for catechol parti-
cipation in the selectivity-determining step of the Stetter reaction.
When chiral, binapthyl-derived catechol 14b is used as an addi-
tive, enantioselectivity of product 9aa improves from 89% ee to
95% ee with ðS;RÞ-precatalyst 4b but shows no change with ðR;SÞ
precatalyst ent-4b (Table 4, entries 5 and 6). When catechol 14a
is substituted with acidic phenol 14c, no improvement in enan-
tioselectivity is observed (Table 4, entry 6).
Entry
Alkyne (9)
9∶15*
Major product (9)
Having explored the scope and selectivity of our Michael/Stet-
ter reaction between DMAD and a variety of salicylaldehydes,
we focused on incorporation of unsymmetrical alkynes as Michael
acceptors in this cascade. Ketoalkynoates 8b and 8c participate in
the one-step reaction with salicylaldehyde (7a) to give moderate
yields of products 9ab and 9ac regioselectively but with low enan-
tioselectivity (Table 5, entries 1 and 2). Attenuation of alkyne elec-
trophilicity by substitution of the aryl ketone with phenethyl
ketone 8d improved the enantioselectivity of major product 9ad
(Table 5, entry 3), but resulted in formation of a second regioi-
somer 15ad in ∼10% yield (see SI Text). Interestingly, minor regioi-
1
2
3
Table 4. Catechol effect on enantioselectivity in the one-pot, two-
step Michael/Stetter reaction
O
CO2Me
1) 11 (20 mol %)
2) 4 (20 mol %)
O
CO2Me
CO2Me
additive (10 mol %)
R
R
O
OH
CO2Me
PhMe, 0
C
7
8a
9
ee, %
Yield, % W/o additive W/additive
Entry
7
Additive
4
1
2
3
4
5
6
7a
7f
7h
7a
7a
14a
14a
14a
14b
14b
4b
4b
4b
4b
ent-4b
4b
63
78
75
63
73
60
89
85
85
89
−89
89
93
90
93
95
−89
89
4‡
7a 14c (1 equiv)
OH
*Product ratios determined by 1H NMR of the unpurified reaction mixture.
†Yield of 9ad and 15ad determined by 1H NMR with reference to 2,6-Di-tert-
butyl-4-methylphenol.
O
N
Br
OH
OH
OH
Br
‡Phosphonate 9ae was prepared according to the one-pot, two-step protocol
(see SI Text).
N
N
C6F5
BF4
ent-4b
Br
14c
§Phosphonate 9ae could not be separated from a minor impurity which
coeluted in multiple solvent systems.
OH
14b
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only in isolation of starting material and decomposition products
(Eq. 6) (59). Nevertheless, we were encouraged to try other
modes of entry into 16b. Shi and Shi have shown that activated
allenes behave as alkyne surrogates in a DABCO-catalyzed con-
jugate addition reaction with salicylaldehyde (59). Indeed, we
were delighted to find that subjection of allenone 18a and alleno-
ate 18b to our one-pot, two-step protocol in a variety of solvents
gave benzofuranone products 19a and 19b in moderate yields and
good to excellent enantioselectivities (Table 6).
olefin geometry contributes significantly to Stetter selectivity.
O
CO2Me
CO2Me
11 (20 mol %)
PhMe, 0
8a
C
O
CO2Me
12aa
~ 20:1 E/Z a
CO2Me
O
+ or
[7]
OH
O
7a
CO2Et
CO2Et
11 (20 mol %)
PhMe, 23
Previous Work (ref. 47)
18a
C
O
Me
16b
O
O
4b (20 mol %)
NEt3 (2 equiv)
CO2Me
Et
~ 20:1 E/Z
Et
CO2Me
[5]
O
O
PhMe, 25
C
C(O)R
O
O
16a
19
11 (20 mol %)
PhMe, 0
C(O)R
96% yield
97% ee
C
[8]
[9]
CO2R
8b-d
O
CO2R
OH
7a
12ab-ad
O
CO2Et
O
1:1 - 1:2 E/Z
CO2Et
Me
O
11 (20 mol %)
PhMe, 23
+
4b (20 mol %)
11 (20 mol %)
CO2Me
CO2Me
O
[6]
C
OH
Me
O
CO2Me
CO2Me
PhMe, 0
C
7a
17
16b
< 5% yield
O
O
12aa
9aa
~ 20:1 E/Z
93% yield
84% ee
We hoped to understand why certain substrates (DMAD,
allenoate 18b) react with much greater enantioselectivity than
others (ketoalkynoates 8b and 8c). A factor that has been shown
to influence Stetter enantioselectivity is olefin geometry (46, 47).
Although intermediate aldehydes 12aa and 16b derived from
DMAD and allenoate 18b form with near perfect E-selectivity
under our conditions (Eq. 7), intermediate aldehydes derived from
ketoalkynoate substrates (8b-d) are observed as unselective mix-
tures of E∕Z isomers (Eq. 8). For a number of Stetter scaffolds, the
E-isomer has been shown to react in higher yield and with greater
enantioselectivity than the corresponding Z-isomer (46, 47). To
examine whether a relatively high Z∕E ratio could contribute to
the low enantioselectivities obtained for ketoalkynoate substrates
8a-c, we subjected a 6.5∶1 Z∕E mixture (60) of intermediate
aldehyde 12aa to our established Stetter conditions. Whereas E
isomer 12aa reacts to afford product 9aa in 84% ee, Z-enriched
12aa gives 9aa in only 29% ee and in appreciably lower yield
(Eq. 9). The disparity in enantioselectivity across batches of
intermediate aldehyde 12aa reinforces previous observations that
66% yield
29% ee
~ 1:6.5 E/Z
Influence of olefin geometry on Stetter enantioselectivity (aE∕Z
ratios determined by H NMR).
1
In summary, we have described a unique and scalable one-pot
procedure for the highly enantioselective preparation of benzofur-
anone products in moderate yields from simple starting materials.
We have demonstrated that the one-pot Michael/Stetter protocol
is superior to the two-step procedure with respect to enantioselec-
tivity, and we have expanded on this observation to show that
catechol additives improve enantioselectivity in the context of
both two-pot and one-pot, two-step reactions. Moreover, we have
identified olefin geometry as an important factor influencing Stet-
ter enantioselectivity. Finally, we have illustrated that activated
allenes behave as competent, E∕Z-selective Michael acceptors
in our one-pot, two-step reaction to provide access to alkyl-substi-
tuted benzofuranones 19 in moderate to excellent enantioselectiv-
ities. Investigations aimed at generalizing this concept are
currently underway.
Table 6. One-pot, two-step Michael/Stetter reaction with activated
allenes
O
O
C(O)R
Materials and Methods
General methods, detailed experimental procedures, and characterization
data for the compounds described in this article can be found in the
SI Text, which is available free of charge on the PNAS web site.
1) 11 (20 mol %), T1
2) 4b (20 mol %), T2
Me
C(O)R
+
O
solvent
OH
7a
18
19
General Procedure for the Multicatalytic Michael/Stetter Reaction. A 1-dram
vial was equipped with a magnetic stir bar under argon and charged sequen-
tially with DMAD (8a) (21 mg, 0.15 mmol), salicylaldehdyde 7 (0.16 mmol), and
triazolium salt 4b (14 mg, 0.030 mmol). Toluene (1.5 mL) was added, and the
mixture was cooled to 0 °C. Quinuclidine (11) (3.0 mg, 0.030 mmol) or DABCO
(10) (3.0 mg, 0.030 mmol) was added in one portion, and the reaction was
monitored by TLC (hexanes/acetone). When the reaction was judged to be
complete, the mixture was quenched with glacial acetic acid (1–2 drops),
filtered through a plug of silica with Et2O (∼40 mL), and concentrated in
vacuo. The resulting product 9 was purified via flash chromatography.
Entry 18 Solvent T1, °C T2, °C
Product (19)
Yield, % ee, %
O
Me
O
1
2
18a THF
18b PhMe
23
23
0
60
50
78
98
19a
19b
C(O)Me
O
Me
23
O
Procedure for the Preparation of 9aa on 7.0 mmol Scale. A 250-mL, flame-dried,
round-bottom flask was charged with triazolium salt 4b (164 mg, 0.350 mmol)
and evacuated for 3 min, then filled with argon. After the evacuation
procedure was repeated an additional two times, DMAD (8a) (1.01 g,
7.12 mmol), salicylaldehyde (7a) (933 mg, 7.64 mg), and toluene (72 mL) were
added sequentially, and the reaction mixture was cooled to 0 °C. Quinuclidine
CO2Et
3
4
18b PhMe 110 110
18b CH2CI2 23 23
19b
19b
50
59
89
96
20670
∣
www.pnas.org/cgi/doi/10.1073/pnas.1002830107
Filloux et al.

(11) (156 mg, 1.40 mmol) was added portionwise to the reaction mixture. After
it was allowed to stir at 0 °C for 9 h, the reaction was quenched with glacial
acetic acid (150 μL) and poured directly onto a silica gel column (5∶1 − 1∶1
hexanes/EtOAc) to give 1.48 g (79% yield) of 9aa as a clear, amorphous solid.
ACKNOWLEDGMENTS. We thank Donald Gauthier (Merck) for a generous
gift of aminoindanol, and Amgen for unrestricted support. We acknowledge
Nick Emmendorfer (Colorado State University) for early experiments. We
gratefully acknowledge the National Institute of General Medical Sciences
(GM72586) and The Herman Frasch Foundation for support of this research.
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Filloux et al.
PNAS
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November 30, 2010
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vol. 107
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