Scope of the asymmetric intramolecular stetter reaction catalyzed by chiral nucleophilic triazolinylidene carbenes

Article abstract of DOI:10.1021/jo702313f

(Chemical Equation Presented) A highly enantioselective intramolecular Stetter reaction of aromatic and aliphatic aldehydes tethered to different Michael acceptors has been developed. Two triazolium scaffolds have been identified that catalyze the intramo

Full text of DOI:10.1021/jo702313f

VOLUME 73, NUMBER 6
MARCH 21, 2008
© Copyright 2008 by the American Chemical Society
Scope of the Asymmetric Intramolecular Stetter Reaction Catalyzed
by Chiral Nucleophilic Triazolinylidene Carbenes
Javier Read de Alaniz, Mark S. Kerr, Jennifer L. Moore, and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
roVis@lamar.colostate.edu
ReceiVed NoVember 3, 2007
A highly enantioselective intramolecular Stetter reaction of aromatic and aliphatic aldehydes tethered to
different Michael acceptors has been developed. Two triazolium scaffolds have been identified that catalyze
the intramolecular Stetter reaction with good reactivity and enantioselectivity. The substrate scope has
been examined and found to be broad; both electron-rich and -poor aromatic aldehydes undergo cyclization
in high yield and enantioselectivity. The tether can include oxygen, sulfur, nitrogen, and carbon linkers
with no detrimental effects. In addition, the incorporation of various tethered Michael acceptors includes
amides, esters, thioesters, ketones, aldehydes, and nitriles. The catalyst loading may be reduced to 3 mol
% without significantly affecting the reactivity or selectivity of the reaction.
Introduction
The synthetic utility of the acyl-anion equivalent has been
extended to the formation of 1,4-dicarbonyl compounds em-
ploying Michael acceptors as the electrophilic partner, a
transformation known as the Stetter reaction.3 The most com-
monly used (pre)catalysts for the achiral Stetter reaction are
alkali metal cyanide or thiazolium salts in the presence of base.
The achiral reaction proceeds well with a wide range of
substrates. Michael acceptors that contain â-substituents often
result in diminished reactivity and are typically restricted to
The inversion of the normal mode of reactivity of aldehydes
catalyzed by cyanide or heteroazolium salt derived carbenes has
emerged as a synthetically useful way of constructing carbon-
carbon bonds.1 Two catalytic reaction processes that employ
umpolung reactivity of aldehydes are the benzoin and Stetter
reactions. The key element of the benzoin and Stetter reactions
is the polarity reversal of the carbonyl initiated by nucleophilic
attack of the catalyst to an aldehyde generating an acyl anion
equivalent that can facilitate the formation of a carbon-carbon
bond. The benzoin reaction results from the addition of the acyl-
anion equivalent to another aldehyde molecule resulting in the
formation of R-keto-alcohols. Due to problems with chemose-
lectivity, this reaction is often limited to homocoupling of
aldehydes.2
(2) For recent examples of an asymmetric benzoin reaction, see: (a)
Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1 1998, 1891-
1893. (b) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743-
1745. An intramolecular crossed-benzoin reaction has been demonstrated;
see: (c) Enders, D.; Niemeier, O.; Balensiefer, T. Angew. Chem., Int. Ed.
2006, 45, 1463-1467. (d) Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki,
K. Angew. Chem., Int. Ed. 2006, 45, 3492-3494. For an elegant solution
to the intermolecular cross-benzoin chemoselectivity problem, see: (e)
Linghu, X.; Potnick, J. R.; Johnson, J. S. J. Am. Chem. Soc. 2004, 126,
3070-3071.
(1) For reviews, see: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res.
2004, 37, 534-541. (b) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43,
1326-1328. (c) Pohl, M.; Lingen, B.; Muller, M. Chem. Eur. J. 2002, 8,
5288-5295. (d) Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007,
107, 5606-5655. (e) Rovis, T. Chem. Lett. 2008, 2-7.
(3) (a) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407-496. (b)
Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632-2634. (c) Webber,
P.; Krische, M. J. Chemtracts: Org. Chem. 2007, 19, 262.
10.1021/jo702313f CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/27/2008
J. Org. Chem. 2008, 73, 2033-2040
2033

de Alaniz et al.
chalcones or other highly activated alkenes. The asymmetric
Stetter reaction has been limited to only two examples prior to
2002.4
Enders and co-workers were the first to report an asymmetric
intramolecular Stetter reaction in 1996.4b Utilizing chiral tria-
zolium salt 2 as a pre-catalyst, the products are obtained in
moderate yield and enantioselectivity, eq 1. Despite the moderate
selectivity, the implementation of a chiral triazolinylidene
carbene in the asymmetric Stetter reaction laid the foundation
for future work.
FIGURE 1. Chiral triazolium salts.
formed stereocenters can be controlled by the stoichiometric
addition of a chiral thiourea with the desired product formed in
74% ee.
We have recently developed a family of chiral triazolium salts
that incorporate readily available chiral primary amines into a
rigid framework (Figure 1).13 Upon deprotonation, these tria-
zolium salts form carbenes which catalyze the asymmetric
intramolecular Stetter reaction. In the early stage of this research,
we hypothesized that an enantioselective intramolecular Stetter
reaction could be developed by tuning the electronic and steric
environment of the triazolium catalyst. In our initial report, we
illustrated the reduction of this concept to practice utilizing 10-
20 mol % of the aminoindanol-derived catalyst 4.14 In this paper,
we report a full investigation of the scope and limitations of
the intramolecular Stetter reaction with aromatic and aliphatic
aldehydes tethered to a variety of R,â-unsaturated Michael
acceptors. We also disclose the results using phenylalanine-
derived catalyst 6 and illustrate the similarities and differences
between the two chiral bicyclic catalysts in the asymmetric
intramolecular Stetter reaction. Furthermore, we demonstrate
that the catalyst loading can be reduced to 3 mol % without
significantly affecting the efficiency or selectivity of the reaction.
Subsequent to our first communication in this area,5 Bach6
and Miller7 have independently described the use of chiral
thiazolium salts as pre-catalysts for the asymmetric intramo-
lecular Stetter reaction. The salicylaldehyde-derived substrate
1 initially reported by Ciganek8 for the intramolecular Stetter
reaction has become the standard test substrate to compare the
efficiency of different catalyst architectures. Bach and co-
workers have employed a novel axially chiral N-arylthiazolium
salt to obtain Stetter products in moderate enantioselectivity.
Miller found that thiazolium salts embedded in a peptide
backbone could impart modest enantioselectivity on the in-
tramolecular Stetter reaction. Very recently, Tomioka has
reported a C2-symmetric imidazolinylidine catalyst for the Stetter
reaction, active and modestly enantioselective even at 110 °C.9
In a related process, Johnson and co-workers have developed
an asymmetric metallophosphite-catalyzed intermolecular Stet-
ter-like reaction employing acyl silanes.10 Acyl silanes are
effective aldehyde surrogates capable of forming an acyl anion
equivalent after a [1,2] Brook rearrangement.11 Taking advantage
of this concept, Johnson was able to fashion the catalytic
enantioselective synthesis of 1,4-dicarbonyls in 89-97% ee and
good chemical yields for R,â-unsaturated amides. Scheidt and
co-workers have recently reported the application of silyl-
protected thiazolium carbinols as stoichiometric carbonyl anions
for the intermolecular acylation of nitroalkenes.12 The newly
Results and Discussion
In our initial communication,5 we reported that the asym-
metric intramolecular Stetter reaction may be catalyzed by 20
mol % of triazolium salts 4 and 6 utilizing 20 mol % KHMDS
as base in xylenes. Catalysts 4-7 each provide the Stetter
adducts with good selectivity. In particular, aminoindanol-
derived catalyst 4 and phenylalanine-derived catalyst 6 provide
complementary reactivity and selectivity in a number of
instances. This fortuitous relationship enabled the development
of the scope of the intramolecular Stetter reaction utilizing both
triazolium catalysts. We initially disclosed the results of the
asymmetric intramolecular Stetter reaction utilizing triazolium
salt 4, as it provides slightly higher enantioselectivity than the
corresponding triazolium salt 6. It is important to note, however,
that both triazolium salts perform the asymmetric Stetter reaction
with high enantioselectivity and excellent reactivity. In general,
the aminoindanol chiral scaffold affords the desired product in
modestly higher enantioselectivity, entries 1-13 (Table 1).
Conversely, the all-carbon phenylalanine-derived scaffold gener-
ally affords higher yields (compare entries 7 vs 8, 9 vs 11).
(4) (a) Enders, D.; Breuer, K. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Ed.; Springer: New York, 1999;
Vol. 3, pp 1093-1102. (b) Enders, D.; Breuer, K.; Runsink, J.; Teles, J. H.
HelV. Chim. Acta 1996, 79, 1899-1902.
(5) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002,
124, 10298-10299.
(6) Pesch, J.; Harms, K.; Bach, T. Eur. J. Org. Chem. 2004, 2025-
2035.
(7) Mennen, S. M.; Blank, J. T.; Tran-Dube`, M. B.; Imbriglio, J. E.;
Miller, S. J. Chem. Commun. 2005, 195-197.
(8) Ciganek, E. Synthesis 1995, 1311-1314.
(9) Matsumoto, Y.; Tomioka, K. Tetrahedron Lett. 2006, 47, 5843-
5846.
(10) (a) Nahm, M. R.; Linghu, X.; Potnick, J. R.; Yates, C. M.; White,
P. S.; Johnson, J. S. Angew. Chem., Int. Ed. 2005, 44, 2377-2379. (b)
Nahm, M. R.; Potnick, J. R.; White, P. S.; Johnson, J. S. J. Am. Chem.
Soc. 2006, 128, 2751-2756.
(13) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Org. Chem. 2005, 70,
5725-5728.
(11) For related examples of acyl silanes in the Stetter reaction, see: (a)
Mattson, A. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am. Chem. Soc. 2004,
126, 2314-2315. (b) Bharadwaj, A. R.; Scheidt, K. A. Org. Lett. 2004, 6,
2465-2468.
(12) Mattson, A. E.; Zuhl, A. M.; Reynolds, T. E.; Scheidt, K. A. J.
Am. Chem. Soc. 2006, 128, 4932-4933.
(14) (a) Reference 5. (b) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004,
126, 8876-8877. (c) Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005,
127, 6284-6289. (d) Reynolds, N. T.; Rovis, T. Tetrahedron 2005, 61,
6368-6378. (e) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2552-
2553. (f) Moore, J. L.; Kerr, M. S.; Rovis, T. Tetrahedron 2006, 49, 11477-
11482. (g) Liu, Q.; Rovis, T. Org. Proc. Res. DeV. 2007, 11, 598-604.
2034 J. Org. Chem., Vol. 73, No. 6, 2008

Asymmetric Intramolecular Stetter Reaction
TABLE 1. Comparison of Different Catalysts on Selectivity and
Reactivity
TABLE 2. Effect of the Tether on the Intramolecular Stetter
Reaction
Table 1 highlights the complementarity between the different
catalyst scaffolds.
Effects of the Tether on the Intramolecular Stetter
Reaction. The length and nature of the tethered Michael
acceptor was examined, and their effects on enantioselectivity
and reactivity were determined (Table 2). The reaction affords
high yields and enantioselectivities for products containing
oxygen, sulfur, and nitrogen tethers (entries 1-4). Removal of
the heteroatom in the linker results in only 35% yield utilizing
catalyst 4 (entry 6). Use of the more reactive catalyst 6 with
this substrate affords the desired product in 92% ee and 90%
yield (entry 8). Increasing the tether length by one methylene
unit results in complete suppression of the reaction and recovery
of unreacted starting material (entry 9). Benzofuranone forma-
tion occurs in good yield using substrate 26 but the product is
formed as a racemate (entry 10). Investigation of the enanti-
oselectivity as a function of conversion reveals that 27 forms
in 80% enantiomeric excess at 10% conversion, with rapid
erosion to 50% ee at 30% conversion. Erosion could arise
via one of two possible scenarios. The benzofuran methine
proton has a pKa of ∼1315 and may epimerize under the basic
reaction conditions. Alternatively, removal of the acidic proton
R to the ester in the product could result in a phenoxide
elimination; subsequent cyclization should result in racemic
product.16
a S-Enantiomer. b R-Enantiomer. c Prone to racemization; see text. d Cata-
lysts 5 and 6 similarly provide no product.
an effort to understand their effects on reactivity and selectivity
(Table 3). Within this series, substitution of hydrogen at the 3
position of the aromatic ring results in decreased selectivity
(entries 2-3). High enantiomeric excesses are obtained with
substrates bearing substitution at the 4- and 5-position of the
aromatic ring (entries 7-18). Substrates bearing electron-
donating groups (EDG) on the ring afford higher enantioselec-
tivities utilizing catalyst 6 relative to those with electron-
withdrawing groups (EWG) in the same position on the aromatic
ring. We observe that electron-withdrawing substituents lead
to partial product racemization under the reaction conditions;17
similar results were also noted by Miller and co-workers.7
Selectivities may be increased by the use of the less basic
catalyst 7, entries 6, 10, and 13.18 Increasing the electron-
donating ability at the 4-position from methoxy to diethylamino
results in an increase of an undesired aldol-elimination side
reaction from trace amounts to 30%, respectively, generating
the seven-membered elimination products (entry 19 illustrates
an example of the elimination product obtained). Subjection of
40 to the reaction conditions in the presence of KHMDS but in
Electronic Effect of the Aromatic Backbone of the Alde-
hyde. Electron-donating and electron-withdrawing substituents
were placed around the aromatic backbone of the aldehyde in
(15) Capon, B.; Kwok, F.-C. J. Am. Chem. Soc. 1989, 111, 5346-5356.
(16) We have shown that benzofuranones lacking the methine proton
may be formed in extremely high enantiomeric excesses (99% ee); this
product epimerizes slowly upon prolonged exposure to DBU suggesting
that phenoxide elimination/conjugate addition is a viable pathway for
racemization; see ref14b,f.
(17) Optically enriched product 35 was resubjected to an intramolecular
Stetter reaction with 20 mol % triazolium salt 6, 20 mol % KHMDS for 24
h and was reisolated as the racemate.
J. Org. Chem, Vol. 73, No. 6, 2008 2035

de Alaniz et al.
TABLE 3. Electronic Effects of the Aromatic Aldehyde on the Intramolecular Stetter Reaction
a R-Enantiomer. b S-Enantiomer.
the absence of catalyst also affords the elimination product,
suggesting a base-induced aldol-type mechanism. However, a
Baylis-Hillman reaction catalyzed by the nucleophilic carbene
cannot be discounted. Application of catalyst 7 completely
suppresses the formation of the undesired side reaction and
affords the desired products in higher yield with good enantio-
selectivity (entry 18).
Variations in the Michael Acceptor. The effects of the
Michael acceptor on the intramolecular Stetter reaction using
catalyst 5 have been reported.19 However, catalyst 5 is unable
to cyclize R,â-unsaturated aldehydes, amides, or Z-enoates. In
addition, the steric effects of the Michael acceptor on the
intramolecular Stetter reaction were not investigated. With
access to a larger family of chiral catalysts, we have re-examined
the effects of the Michael acceptor on reactivity and selectivity
(Table 4). The reaction is remarkably tolerant of a variety of
Michael acceptors, with the successful cyclization of R,â-
unsaturated aldehyde, amide, nitrile, esters, thioesters, and
ketones utilizing catalyst 45. Increasing the steric bulk of the
R,â-unsaturated esters from methyl to tert-butyl results in a slight
increase in selectivity (entries 1-3), an observation also made
by Tomioka.9 Cyclization of the (Z)-R,â-unsaturated methyl
ester 50 can now be achieved albeit with low enantioselectivity
(entry 4). As anticipated, the cyclization of R,â-unsaturated
ketones affords the desired product in excellent overall yield;
however, a decrease in selectivity is evident when moving from
the R,â-unsaturated ethyl ketone 52 to the phenyl ketone 12
(entries 5-6). The R,â-unsaturated thioester 54 and amide 56
are well tolerated in the intramolecular Stetter reaction (entries
7 and 8). The incorporation of the thioester20 and the Weinreb
amide21 offers an excellent handle for further manipulations.
R,â-Unsaturated nitrile 58 was subjected to the reaction as an
inseparable 1:1 mixture of E/Z olefin isomers and was found
to afford the desired product in good yield and 80% enantiose-
lectivity. The enantioselectivity of the product is similar to the
reaction commencing from isomerically pure (E)-R,â-unsatur-
ated nitrile 60 (entry 10). This unexpected result clearly
illustrates that the Z olefin isomer is tolerated but the result-
(18) Reactions that contain an EWG on the aromatic backbone typically
proceed to completion in 15-60 min. If the reaction is allowed to stir for
24 h, the product is isolated with enantiomeric excess between 67-80%.
In addition, we briefly examined if erosion occurs during purification by
column chromatography. Optically enriched 35 was dissolved in toluene
and stirred with silica gel and the enantioselectivity decreased from 90%
to 66% ee. Erosion of enantioselectivity could be avoided by treating the
silica gel with 15% acetic acid prior to column chromatography.
(19) Kerr, M. S.; Rovis, T. Syntlett 2003, 1934-1936.
(20) Tokuyama, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T.
Tetrahedron Lett. 1998, 39, 3189-3192.
(21) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815-
3818.
2036 J. Org. Chem., Vol. 73, No. 6, 2008

Asymmetric Intramolecular Stetter Reaction
TABLE 4. Effect of the Michael Acceptor on the Intramolecular Stetter Reaction
a 20 mol % of catalyst 5 was used. b Opposite antipode of the chiral triazolium salt 45 was used.
ing enantioselectivity depends on the nature and size of the
Michael acceptor (vide infra). The R,â-unsaturated aldehyde
affords the desired product in 50% isolated yield, but only
30% ee.
Practical Considerations. Throughout the course of our
investigations, we have noted that both water and air have
detrimental effects on the outcome of the intramolecular Stetter
reaction. The requirements for excessive care in the setup or
execution of this reaction would clearly constitute an impedi-
ment to its application in other laboratories, and we therefore
spent some effort rendering the process more user-friendly. To
that end, we conducted the optimized Stetter reaction open to
the atmosphere, entry 2 in Table 6. Enantioselectivities are not
affected, but chemical yield is significantly lower, a situation
we ascribe to premature catalyst decomposition.22,23 We further
note that utilizing ACS grade toluene as the solvent, drawn
directly from the bottle without any purification, results in
decreased reaction efficiency and formation of an undesired
aldol product 73 in 30% yield.
Expanding the Scope To Include Aliphatic Aldehydes.
After successfully performing a highly enantioselective intramo-
lecular Stetter reaction on a broad range of aromatic aldehydes,
we turned our attention to the potentially more difficult aliphatic
aldehydes. Aliphatic aldehydes may bear acidic hydrogens R
to the carbonyl and we were initially concerned that this could
pose a problem. To our gratification, a number of aliphatic
aldehydes bearing acidic hydrogens participate in the intramo-
lecular Stetter reaction (Table 5). Cyclopentanones 17 and 64
are each generated in excellent yield and selectivity (entries 1
and 2). Nitrogen is tolerated in the tether, affording the desired
product in excellent enantiomeric excess. This reaction thus
offers a new approach toward optically enriched pyrolidinones
such as 66 (entry 3). The intramolecular Stetter reaction
providing cyclohexanone products was more challenging,
presumably due to increased degrees of freedom, and employ-
ment of R,â-unsaturated ethyl esters results in only recovered
starting material (entry 4). However, increasing the electrophilic
nature of the Michael acceptor results in successful cyclization
of cyclohexanones 70 and 72 in good yields and modest to good
enantioselectivities (entries 5 and 6).
(22) One can ascribe the cause of this decomposition to both water and
molecular oxygen. However, we hypothesize that in this particular experi-
ment, oxygen is the real culprit, partly due to Colorado’s arid climate and
therefore a lower concentration of moisture, and partly to our subsequent
observations involving the beneficial effects of argon bubbling through the
solution.
(23) Decomposition products derived from the triazolinylidene carbene
have so far resisted efforts directed towards their isolation and conclusive
identification. Addition of water to the free carbene in an NMR tube
generates a spectrum consistent with an aminal, the product of net water
addition to the carbene carbon.
J. Org. Chem, Vol. 73, No. 6, 2008 2037

de Alaniz et al.
TABLE 5. Aliphatic Aldehydes in the Intramolecular Stetter
Reaction
SCHEME 1. Proposed Catalytic Cycle
enantioselectivity (Table 6, entries 5-7). Despite the slight
decrease in enantioselectivity, the utility of ACS grade toluene
in the presence of MgSO4 makes this process synthetically
attractive, especially when anhydrous toluene is not readily
available.
Since a slight erosion of enantioselectivity is observed in the
presence of water scavengers, large-scale reactions with de-
creased catalyst loading are routinely conducted with anhydrous
toluene. To exclude adventitious amounts of oxygen, argon is
bubbled through the solution of toluene before and during the
course of the reaction. Using this protocol, subjection of 2.2 g
(9.4 mmol) of 8 to a solution of 3 mol % triazolium salt 6 and
corresponding amounts of base in anhydrous toluene under
argon results in 97% isolated yield of the desired product in
89% ee (eq 8).24
TABLE 6. Effect of Water and Oxygen on the Stetter Reaction
entry
change from above conditions
yield (%)
ee (%)
1
2
3
4
5
6
7
none
open to air
94
42
70a
0
90
80
90
90
90
82
NA
85
82
PhMe from bottle (ACS grade)
PhMe saturated with H2O
PhMe (ACS) + MS 4 Å
PhMe (ACS) + Na2SO4
PhMe (ACS) + MgSO4
Discussion
The Stetter reaction is likely intimately related to the much
better studied benzoin reaction and a proposed mechanism is
illustrated in Scheme 1.25 According to the proposed mechanism,
intermediate I results from nucleophilic attack of the carbene
into the aldehyde. Subsequent proton transfer affords the acyl
anion equivalent II, whose resonance structure is the enolamine,
87
a Compound 73 isolated in 30% yield.
(24) Enders has illustrated that triazolinylidene carbenes react with
molecular oxygen, forming cyclic ureas; see: (a) Enders, D.; Breuer, K.;
Runsink, J.; Teles, J. H. Liebigs Ann. Chem. 1996, 2019-2028. (b) Enders,
D.; Breuer, K.; Teles, J. H.; Gielen, H. J. Prakt. Chem. 1997, 339, 397-
399.
(25) Mechanism of the thiamine-catalyzed benzoin condensation reac-
tion: (a) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719-3726. (b) Breslow,
R.; Kim, R. Tetrahedron Lett. 1994, 35, 699-702. (c) White, M. J.; Leeper,
F. J. J. Org. Chem. 2001, 66, 5124-5131. Mechanism of the cyanide-
catalyzed reaction: (d) Lapworth, A. J. Chem. Soc. 1903, 83, 995-1005.
(e) do Amaral, L.; Bull, H. G.; Cordes, E. H. J. Am. Chem. Soc. 1972, 94,
7579-7580. For the mechanism of the cyanide-catalyzed crossed silyl
benzoin reactions, see: (f) Linghu, X.; Bausch, C. C.; Johnson, J. S. J.
Am. Chem. Soc. 2005, 127, 1833-1840.
We speculated that trace water in commercial toluene may
have been the cause of this reactivity difference. Indeed, the
use of water-saturated toluene as solvent results in no reac-
tion, entry 4 in Table 6. A number of common water scavengers
were surveyed in an attempt to provide a practical solution.
The addition of molecular sieves, sodium sulfate (Na2SO4),
or magnesium sulfate (MgSO4) results in a decrease in reac-
tion time, increased yields and suppression of the undesired
side reaction, but provides the product in slightly reduced
2038 J. Org. Chem., Vol. 73, No. 6, 2008

Asymmetric Intramolecular Stetter Reaction
FIGURE 2. Proposed stereochemical model.
commonly referred to as the Breslow intermediate. Carbon-
carbon bond formation results from nucleophilic attack of the
Breslow intermediate II into a Michael acceptor, generating
enolate III. A stereochemical model to rationalize observed
stereochemistry will focus on this step. Enolate protonation
followed by release of the catalyst generates the 1,4-dicarbonyl
and closes the catalytic cycle.
The absolute configurations of products 3 and 17 formed with
catalyst 6 were determined to be S by comparison of the
measured optical rotation value with the corresponding literature
data.26 The absolute configurations of 49 and 55 were assigned
by chemical correlation, with the rest assigned by analogy;
aliphatic substrate 7227 was assigned by chemical correlation
with the rest assigned by analogy to 17.28 In a computational
study modeling the transition state for the benzoin reaction with
a related triazolinylidene carbene, Dudding and Houk note that
the E isomer of the Breslow intermediate is more stable.29,30
Our working model to explain the stereochemical outcome of
the reaction, illustrated in Figure 2,31 thus assumes that carbon-
carbon bond formation takes place from the E isomer of the
Breslow intermediate. The chiral residue sterically shields the
si face of the Breslow intermediate thus gearing the Michael
acceptor toward the enolamine’s re face. The enantiodiscrimi-
nating step would then result from attack on either the re or si
face of the tethered Michael acceptor. Attack on the re face of
the Michael acceptor results in the observed stereochemistry
as depicted by path B. Subtle differences between models A
and B are apparent. The use of the nonpolar solvent toluene
may promote a requirement for minimal charge separation in
the transition state, placing the carbonyl oxygen in close
proximity to the triazolium carbene carbon atom, models Aq
and Bq. We speculate that a steric clash between the ester
substituent and the underside of the morpholine ring may
destabilize model A in relation to B.
(26) (a) See ref 4b. (b) Wang, S.; Chen, G.; Kayser, M. M.; Iwaki, H.;
Lau, P. C. K.; Hasegawa, Y. Can. J. Chem. 2002, 80, 613-621.
(27) Ebinger, A.; Heinz, T.; Umbricht, G.; Pfaltz, A. Tetrahedron 1998,
54, 10469-10480.
(28) Our original assignment for the absolute stereochemistry of 17 was
based on the assumption that the aliphatic series was analogous to the
aromatic series (see ref 14a). This has since proved incorrect. The correct
absolute chemistry is assigned by comparison to ref 26b.
(29) Dudding, T.; Houk, K. N. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
5770-5775.
(30) The proposed transition state is further supported by a recent example
by Enders and co-workers utilizing chiral triazolium salts in an asymmetric
intramolecular crossed-benzoin reaction. See ref 2c.
(31) This model is an MM2 minimization (Chem 3D) of the catalyst
framework and substrate, followed by simple manipulation of the substit-
uents within that software, and is meant to serve as a mnemonic rather
than a transition state approximation. We are currently engaged in a
collaboration to provide theoretical and computational support for this model.
J. Org. Chem, Vol. 73, No. 6, 2008 2039

de Alaniz et al.
(0.030 mmol) of KHMDS, and 40.0 mg (0.150 mmol) of 12 were
reacted for 24 h. Workup afforded 37.2 mg (94%) of the desired
product as a colorless oil: Rf (1:1 hexane to ethyl acetate) ) 0.7;
[R]23D ) -36.2 (CHCl3); HPLC analysis - Chiralcel OD-H column
(90:10 hexanes to isopropanol, 1.0 mL/min). Major enantiomer:
10.9 min, minor enantiomer: 13.9 min; 1H NMR (400 MHz, CDCl3)
δ 7.99-7.97 (2H, m), 7.88 (1H, m), 7.56 (1H, m), 7.49-7.44 (3H,
m), 7.01 (1H, m), 6.97 (1H, m), 4.62 (1H, dd, J) 5.3, 11.1 Hz),
4.29 (1H, dd, J)11.3, 11.5 Hz), 3.69 (1H, dd, J) 3.8, 18.1 Hz),
3.58 (1H, dddd, J) 3.8, 5.3, 8.5, 11.9 Hz), 3.00 (1H, d, J) 8.3,
17.9 Hz); 13C NMR (100 MHz, CDCl3) δ 197.2, 193.6, 162.0,
136.6, 136.2, 133.6, 128.9, 128.3, 127.6, 121.6, 120.8, 118.0, 70.6,
42.0, 34.5; IR (NaCl, CH2Cl2) 1680, 1607, 1483 cm-1; HRMS
(FAB+) calcd for C17H15O3 (M + H)+ 267.1016, found 267.1028.
(2R)-3-Ethoxycarbonylmethyl-4-oxopyrrolidine-1-carboxyl-
ic Acid Benzyl Ester (66). According to the general procedure,
12.0 mg (0.032 mmol) of 6 and 65.0 µL (0.032 mmol) of KHMDS
and 50.0 mg (0.164 mmol) of 65 were reacted for 24 h. Workup
afforded 40.0 mg (80%) of the desired product as a colorless oil:
This model provides a suitable rationale for several of our
experimental observations. A larger ester on the Michael
acceptor provides a slight increase in selectivity (95% ee for
methyl ester, 97% ee for tert-butyl ester, entries 1 and 3, Table
4), due to a more deleterious steric interaction in model A. The
Z-enoate substrate, on the other hand, provides much lower
selectivity (entry 4, Table 4). Exchange of the R-proton and
ester carbonyl in model B results in a significant steric
interaction with the phenyl substituent on the triazole ring, thus
significantly disfavoring this orientation. Last, our observation
that enenitriles provide lower selectivities, apparently indepen-
dent of olefin geometry may also be rationalized (entries 9 and
10, Table 4). The considerably smaller size of the cyano group
reduces steric interactions in both models A and B; it is also
apparent that its smaller size may be accommodated in the
Z-isomer as well.
Rf (1:1 hexane to ethyl acetate) ) 0.5; [R]23 ) + 23.1 (CHCl3);
Conclusion
D
GC analysis (B-DM column 80 °C for 120 min then ramp to 120
°C over 10 min). Minor enantiomer: 144.0 min, major enanti-
omer: 148.7 min; 1H NMR (300 MHz, C6D5CD3 (80 °C)) δ 7.24-
7.10 (5H, m), 5.09 (2H, s), 3.92-3.80 (4H, m), 3.58 (1H, dd, J )
18.9, 18.9 Hz), 3.42 (1H, dd, J ) 18.8, 18.8 Hz), 2.98 (1H, dd, J
) 10.5, 9 Hz), 2.34-2.13 (2H, m); 13C NMR (100 MHz, CDCl3)
δ 211.1, 171.1, 169.0, 136.5, 128.8, 128.4, 128.3, 67.5, 61.4, 52.7,
The scope of a highly enantioselective intramolecular Stetter
reaction has been described. The reaction proceeds at room
temperature with a variety of substrates providing 1,4-dicarbonyl
compounds in good chemical yield and the catalyst loading can
be decreased to 3 mol % without loss of reactivity or enantio-
selectivity. The substrate scope has been extended to include
aliphatic aldehydes as well as electron rich and poor aromatic
aldehydes. In addition, the incorporation of various tethered
Michael acceptors has been improved and now includes amides,
esters, thioesters, ketones, aldehydes, and nitriles. Importantly,
we have identified triazolium pre-catalysts bearing electron-
deficient aryl groups that consistently provide better yields and
selectivities for this transformation.
48.3, 44.0, 33.0, 14.3; IR (NaCl, CH2Cl2) 1760, 1709, 1418 cm-1
;
HRMS (FAB+) calcd for C16H20NO5 (M + H)+ 306.1336, found
306.1333.
Acknowledgment. We thank the National Institute of
General Medical Sciences (GM72586) and the National Insti-
tutes of Health (minority supplement to J.R.) for support. J.R.
thanks the National Institutes of Health (Ruth L. Kirschstein
Minority Pre-doctoral fellowship) and Colorado PEAKS AGEP
(graduate fellowship). M.S.K. thanks Boehringer-Ingelheim for
a graduate fellowship. J.L.M. thanks the National Institutes of
Health (Ruth L. Kirschstein Minority Pre-doctoral fellowship).
T.R. gratefully acknowledges Merck Research Laboratories,
GlaxoSmithKline, Amgen, Johnson & Johnson, Eli Lilly, and
Boehringer-Ingelheim for support. T.R. thanks the Monfort
Family Foundation for a Monfort Professorship. T.R. is a fellow
of the Alfred P. Sloan Foundation. We thank Michael C. Hillier
and Donald Gauthier (Merck) for a generous gift of aminoin-
danol.
Experimental Section
General Procedure for the Asymmetric Intramolecular Stet-
ter Reaction. A flame dried round-bottom flask was charged with
triazolium salt (0.2 equiv) and toluene (5 mL). To this solution
was added KHMDS (0.5 M in toluene prepared prior to use from
0.05 g of KHMDS in 0.5 mL of toluene) (0.2 equiv) via syringe,
and the solution was stirred at ambient temperature for 5 min. A
solution of the substrate (1 eq, 0.12 mmol) in toluene (2 mL) was
added. The resulting solution was allowed to stir at ambient
temperature and monitored by TLC. The reaction mixture was
placed directly onto a silica gel column. The desired product was
purified by flash column chromatography, eluted with a suitable
solution of hexane and ethyl acetate (typically 4:1). Evaporation
of solvent afforded analytically pure product.
Supporting Information Available: Detailed experimental
procedures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(2S)- 3-(2-Oxo-2-phenylethyl)chroman-4-one (13). According
to the general procedure, 14.0 mg (0.030 mmol) of 45, 60.0 µL
JO702313F
2040 J. Org. Chem., Vol. 73, No. 6, 2008