Organocatalytic asymmetric conjugate addition to allenic esters and ketones

Article abstract of DOI:10.1021/ja710689c

The first example of an organocatalytic enantioselective conjugate addition of cyclic β-ketoesters and glycine imine derivatives to electron-deficient allenes is described. We disclose that the corresponding chiral β,γ-unsaturated carbonyl compounds are formed exclusively under phase-transfer conditions using either cinchona-alkaloid-derived or biphenyl-based chiral quaternary ammonium salts as catalysts. The scope of the reaction for β-ketoesters is outlined for allenes having a ketone or ester motif as electron-withdrawing group as well as different substituents in the 3-position, giving the optically active products in high yields and excellent diastereo- and enantioselectivities (90-96% ee). The conjugate addition also proceeds for a number of cyclic β-ketoesters having different ring sizes, ring systems, and substituents in high yields and enantioselectivities. Glycine imine derivatives also undergo the asymmetric conjugate addition to electron-deficient allenes in high yields and with enantioselectivities in the range of 60-88% ee, thus providing a rapid entry to optically active α-vinyl-substituted α-amino acid derivatives. It is shown that the enantioselectivity is strongly dependent on the size of the ester moiety of the nucleophile in combination with the catalytic system used. The high synthetic value of the chiral products arising from these new catalytic processes is demonstrated by two straightforward transformations leading in one case to optically active hexahydrobenzopyranones and in the other to substituted pyroglutamates (γ-lactames).

Full text of DOI:10.1021/ja710689c

Published on Web 03/15/2008
Organocatalytic Asymmetric Conjugate Addition to Allenic
Esters and Ketones
Petteri Elsner, Luca Bernardi, Giorgio Dela Salla, Jacob Overgaard, and
Karl Anker Jørgensen*
Danish National Research Foundation, Center for Catalysis, Department of Chemistry,
Aarhus UniVersity, DK-8000 Aarhus C, Denmark
Received December 4, 2007; E-mail: kaj@chem.au.dk
Abstract: The first example of an organocatalytic enantioselective conjugate addition of cyclic â-ketoesters
and glycine imine derivatives to electron-deficient allenes is described. We disclose that the corresponding
chiral â,γ-unsaturated carbonyl compounds are formed exclusively under phase-transfer conditions using
either cinchona-alkaloid-derived or biphenyl-based chiral quaternary ammonium salts as catalysts. The
scope of the reaction for â-ketoesters is outlined for allenes having a ketone or ester motif as electron-
withdrawing group as well as different substituents in the 3-position, giving the optically active products in
high yields and excellent diastereo- and enantioselectivities (90-96% ee). The conjugate addition also
proceeds for a number of cyclic â-ketoesters having different ring sizes, ring systems, and substituents in
high yields and enantioselectivities. Glycine imine derivatives also undergo the asymmetric conjugate addition
to electron-deficient allenes in high yields and with enantioselectivities in the range of 60-88% ee, thus
providing a rapid entry to optically active R-vinyl-substituted R-amino acid derivatives. It is shown that the
enantioselectivity is strongly dependent on the size of the ester moiety of the nucleophile in combination
with the catalytic system used. The high synthetic value of the chiral products arising from these new
catalytic processes is demonstrated by two straightforward transformations leading in one case to optically
active hexahydrobenzopyranones and in the other to substituted pyroglutamates (γ-lactames).
Scheme 1. Products Arising from Conjugate Addition to
Electron-Deficient Alkenes, Allenes, and Electron-Deficient Allenes
in Presence of a Tertiary Phosphine
Introduction
Regarding the significance of carbon-carbon bond formation,
the vinylogous addition to unsaturated carbonyl compounds
displays one of the cornerstones in synthetic organic chemistry.
As a consequence, in the past decades, much attention has been
drawn to the development of asymmetric versions of this type
of reaction. Next to the vinylogous aldol reaction,1 conjugate
additions2 to R,â-unsaturated carbonyl compounds cover a large
part of the tremendous effort in this research area (Scheme 1,
equation a). In these reactions highly functionalized compounds
with up to two chiral centers can be formed, which provides an
excellent opportunity to access complex and valuable intermedi-
ates for asymmetric synthesis. In this context, acroleins,
acrylates, vinyl ketones, and R-nitroalkenes have been studied
extensively as electrophiles for the 1,4-addition of carbon-
centered nucleophiles. Numerous methods have been developed,
especially catalytic asymmetric versions,3 which in many cases
have been successfully applied for the synthesis of biologically
significant molecules, clearly demonstrating the utility of this
transformation.4
In recent years, allenes, in particular electron-deficient allenes,
have emerged as attractive electrophiles in organic synthesis.5
This growing interest is to a large extent due to the development
(1) (a) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew. Chem., Int.
Ed. 2005, 44, 4682. (b) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu,
G. Chem. ReV. 2000, 100, 1929. (c) Martin, S. F. Acc. Chem. Res. 2002,
35, 895. (d) Kalesse, M. Top. Curr. Chem. 2005, 244, 43.
(2) ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
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2001, 171. (b) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033. (c)
ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yama-
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1105-1142. (d) Kanai, M.; Shibasaki, M. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: Weinheim, Germany, 2000;
p 569. For recent reviews on organocatalytic asymmetric conjugate
additions, see: (e) Lelais, G.; MacMillan, D. W. C. Aldrichim. Acta 2006,
39, 79. (f) Vicario, J. L.; Bad´ıa, D.; Carrillo, L. Synthesis 2007, 2065. (g)
Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18,
299. (h) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (i) Sulzer-Mosse,
S.; Alexakis, A. Chem. Commun. 2007, 3123. For recent reviews on metal-
catalyzed asymmetric conjugate additions, see: (j) Lopez, F.; Minnaard,
A. J.; Feringa, B. L. Acc. Chem. Res. 2007, 40, 179. (k) Lopez, F.; Feringa,
B. L. In Asymmetric Synthesis; Christmann, M., Braese, S., Eds.; Wiley-
VCH: Weinheim, Germany, 2007; p 78. (l) Christoffers, J.; Koripelly, G.;
Rosiak, A.; Roessle, M. Synthesis 2007, 1279.
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D.; Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14546. (b) Wang, Y.; Liu,
X.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928. (c) Van Summeren, R.
P.; Moody, D. B.; Feringa, B. L.; Minnaard, A. J. J. Am. Chem. Soc. 2006,
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Chem. Soc. 2004, 126, 96. (e) Shibuguchi, T.; Mihara, H.; Kuramochi, A.;
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Elsner et al.
of efficient methods for the preparation of allenes based on either
classical organic chemistry or organometallic reagents.6 The
conjugate addition to electron-deficient allenes gives rise to â,γ-
unsaturated carbonyl compounds (Scheme 1, eq b) bearing a
nonconjugated double bond as a further functionality available
compared to the 1,4-addition to enoates and enones. This makes
them even more versatile as structural motives and chiral
building blocks for further elaborations. However, since allenes
possess no prochiral center at the â-carbon atom, the chirality
must be induced by their reaction partner(s), which leads as a
consequence to new developments in asymmetric methodology.
This was just recently very effectively underlined by the group
of Shibasaki, who demonstrated that the â,γ-double bond of
allenoates, in situ activated by the addition of dialkylzinc
reagents, can be used within a catalytic asymmetric multicom-
ponent process, serving as a nucleophile to form quaternary
stereocenters via vinylogous aldol addition.7 The same group
and the group of Riant also reported a catalytic asymmetric
reductive aldol reaction of allenic esters to ketones.8
In contrast, if a catalytic amount of a tertiary phosphine is
present, attack of the nucleophile to the electron-deficient allene
occurs at the γ-carbon atom, resulting in an inverse addition
(Scheme 1, eq c). It was shown by Zhang et al. that this
umpolung addition reaction, first described by the group of
Trost9 for alkynoates and by the group of Lu10 for allenoates,
can be performed in a stereoselective fashion with chiral
phosphines and â-ketoesters as nucleophiles.11 The zwitterionic
dipole resulting from addition of a tertiary phosphine to
allenoates can also be used for [3 + 2]-cycloadditions with
electron-deficient alkenes. This reaction was also pioneered by
Lu et al.,12 and progress toward a catalytic asymmetric version
of this kind of annulation was made by the groups of Zhang,13
Fu,14 Wallace,15 and Miller.16 The group of Miller also noted
that the course of this reaction can be changed to give a
conjugate addition product if the phosphine catalyst is exchanged
for an amine catalyst.17
remain scarce,19 we wondered if we could apply asymmetric
organocatalysis to get direct access to enantioenriched â,γ-
unsaturated carbonyl compounds with a vinyl-substituted qua-
ternary carbon center. In this context, asymmetric phase-transfer
catalysis (PTC)20 with, e.g., â-ketoesters as nucleophiles is a
powerful tool, as demonstrated by several highly efficient
transformations developed by our group and others.21 We now
wish to report our efforts in the development of the first
enantioselective, phase-transfer-catalyzed conjugate addition of
cyclic â-ketoesters 1 to electron-deficient allenes 3 (Scheme
2). Furthermore, the utility of the use of allenes for the synthesis
of vinyl-substituted chiral carbon centers prompted us to the
realization of an asymmetric addition of benzophenone imines
222 derived from glycine leading to a very simple and direct
access to pharmaceutically interesting optically active R-vinyl-
substituted R-amino acids 5. Finally, the products 4 and 5 arising
from this catalytic process are shown to be suitable for
subsequent transformations yielding valuable optically active
building blocks, e.g., cis-fused bicyclic lactones and γ-lactames.
Scheme 2. Phase-Transfer-Catalyzed Asymmetric Conjugate
Addition to Electron-Deficient Allenes
Since formation of all-carbon quaternary stereocenters is a
significant challenge in organic chemistry18 and examples of
stereoselective conjugate additions to electron-deficient allenes
(6) For reviews, see: (a) Miesch, M. Synthesis 2004, 746. (b) Hoffmann-Ro¨der,
A.; Krause, N. Angew. Chem., Int. Ed. 2002, 41, 2933. (c) Krause, N.;
Hoffmann-Ro¨der, A. Tetrahedron 2004, 60, 11671.
(7) Oisaki, K.; Zhao, D.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2007,
129, 7439.
(8) (a) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew. Chem.,
Int. Ed. 2006, 45, 1292. (b) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki,
M. Tetrahedron Lett. 2006, 47, 1403. (c) Zhao, D.; Oisaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 14440.
(9) Trost, B. M.; Li, C.-J. J. Am. Chem. Soc. 1994, 116, 3167.
(10) Zhang, C.; Lu, X. Synlett 1995, 645.
(11) Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Org. Chem.
1998, 63, 5631.
(12) (a) Zhang, C.; Lu, X. J. Org. Chem. 1995, 60, 2906. (b) Xu, Z.; Lu, X.
Tetrahedron Lett. 1999, 40, 549. (c) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem.
Res. 2001, 34, 535. (d) Du, Y.; Lu, X.; Yu, Y. J. Org. Chem. 2002, 67,
8901. (e) Du, Y.; Lu, X. J. Org. Chem. 2003, 68, 6463.
(20) For reviews, see: (a) O’Donnell, M. J. In Catalytic Asymmetric Synthesis,
2nd ed.; Ojima, I., Ed.; Wiley-VCH: Weinheim, Germany, 2000; p 727.
(b) Shioiri, T.; Arai, S. In Stimulating Concepts in Chemistry; Vogtle, F.,
Stoddard, J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, Germany,
2000; p 123. (c) Vachon, J.; Lacour, J. Chimia 2006, 60, 266. (d) Gaunt,
M. J.; Johansson, C. C. C.; McNally, A.; Vo, N. T. Drug DiscoVery Today
2007, 12, 8.
(21) (a) Manabe, K. Tetrahedron Lett. 1998, 39, 5807. (b) Manabe, K.
Tetrahedron 1998, 54, 14465. (c) Dehmlov, E. V.; Du¨ttmann, S.; Neumann,
B.; Stammler, H.-G. Eur. J. Org. Chem. 2002, 2087. (d) Ooi, T.; Miki, T.;
Taniguchi, M.; Shiraishi, M.; Takeuchi, M.; Maruoka, K. Angew. Chem.,
Int. Ed. 2003, 42, 3796. (e) Park, E. J.; Kim, M. H.; Kim, D. Y. J. Org.
Chem. 2004, 69, 6897. (f) Bella, M.; Kobbelgaard, S.; Jørgensen, K. A. J.
Am. Chem. Soc. 2005, 127, 3670. (g) Kobbelgaard, S.; Bella, M.; Jørgensen,
K. A. J. Org. Chem. 2006, 71, 4980. (h) Poulsen, T. B.; Bernardi, L.; Bell,
M.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 6551. (i) Poulsen,
T. B.; Bernardi, L.; Alema´n, J.; Overgaard, J.; Jørgensen, K. A. J. Am.
Chem. Soc. 2007, 129, 441. (j) Bernardi, L.; Lo´pez-Cantarero, J.; Niess,
B.; Jørgensen, K. A. J. Am. Chem. Soc. 2007, 129, 5772. (k) Alema´n, J.;
Reyes, E.; Richter, B.; Overgaard, J.; Jørgensen, K. A. Chem. Commun.
2007, 3921.
(13) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am. Chem.
Soc. 1997, 119, 3836.
(14) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006, 45, 1426.
(15) Wallace, D. J.; Sidda, R. L.; Reamer, R. A. J. Org. Chem. 2007, 72, 1051.
(16) Cowen, B. J.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988.
(17) Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125, 12394.
(18) For reviews, see, e.g.: (a) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5363. (b) Christoffers, J.; Baro, A. AdV. Synth. Catal.
2005, 347, 1473. (c) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (d) Corey,
E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
(19) For achiral examples, see: (a) Lucas, S.; Kazmaier, U. Synlett 2006, 255.
(b) Silvestri, M. A.; Bromfield, D. C.; Lepore, S. D. J. Org. Chem. 2005,
70, 8239. (c) Dieter, R. K.; Lu, K. J. Org. Chem. 2000, 65, 8715. (d) Dieter,
R. K.; Lu, K. Tetrahedron Lett. 1999, 40, 4011. (e) Sugita, T.; Eida, M.;
Ito, H.; Komatsu, N.; Abe, K.; Suama, M. J. Org. Chem. 1987, 52, 3789.
For a chiral example, see: El Achqar, A.; Boumzebra, M.; Roumestant,
M. L.; Viallefont, P. Tetrahedron 1988, 44, 5319.
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A R T I C L E S
Results and Discussion
unsaturated carbonyl compounds in comparable high yields and
enantioselectivities of 93% and 94% ee, respectively (entries 1
and 2). Applying the diastereomeric catalyst 6′ allows the
preparation of the opposite enantiomer of the products with
nearly similar results, as exemplified for compound 4a (entry
1). Substitution at the 4-position of the allene was also
investigated. Using the racemic allenes 3c-e gave the corre-
sponding products with a high preference for one diastereomer
(entries 3-5). The phenyl-substituted allenes 3c and 3d thereby
showed slightly better enantioselectivities (93% and 96% ee,
respectively) than the n-butyl-substituted allene 3e (90% ee)
with K2CO3 as the base. This is probably due to the fact that
the reaction with 3e is much faster under identical reaction
conditions, thus suggesting a significant noncatalyzed back-
ground reaction eroding slightly the enantioselectivity. Conse-
quently, the reaction with allene 3e was conducted using
K2HPO4 as the base, which resulted in an elevated reaction time
(4.5 h instead of 3 h) and an increase in enantioselectivity (94%
ee, entry 5).
â-Ketoesters as Nucleophiles. Recently, phase-transfer cata-
lysts 6 and 6′, based on the structural motif of dihydrocinchonine
and dihydrocinchonidine, respectively, were identified to be
effective in a number of different asymmetric transformations
applying cyclic tert-butyl â-ketoesters.21h-k While it was known
that the sterically demanding 9-anthracenylmethyl substituent
at the quinuclidine nitrogen atom amplifies enantioselectivities
in PTC reactions,23 for our system an additional bulky substitu-
ent at the C9-hydroxyl group was crucial to obtain high
enantioselectivities (Chart 1).
Chart 1
The double-bond geometry of the major diastereomers of
compounds 4c-e was determined to be E by analogy with the
X-ray analysis of the N-tosylhydrazone of 5-chloroindanone-
derived â,γ-unsaturated carbonyl compound 4h (see Supporting
Information). This can be rationalized by assuming that the
substituted allene is approaching from the less hindered side to
the Si-face of the enolate formed from the â-ketoester and the
chiral phase-transfer catalyst (Chart 2, right). Additionally,
enhanced 1,3-allylic strain in the formed (Z)-product should
favor formation of the (E)-product (Chart 2). Although the
4-substituted allenes 3c-e were applied as their racemates, there
is only one enantiomer shown in Chart 2 since the axial chirality
of the allene has no impact on the diastereoselectivity.
The generality of this catalytic system and mild reaction
conditions encouraged us to determine whether an asymmetric
conjugate addition to electron-deficient allenes could be achieved.
In preliminary attempts the interplay of base strength and
reaction temperature were identified as crucial parameters in
order to obtain significant conversion (see Supporting Informa-
tion for measurements of base strengths and further discussions),
since strong basic conditions led to competing polymerization
of the allene, leaving the â-ketoester nearly unreacted. In
addition, the formed product was considered to be prone to
isomerize to the thermodynamically favored R,â-unsaturated
carbonyl compound. Apart from one example (vide infra),
double-bond isomerization was never observed. Accordingly,
in our initial experiments with 1-indanone-derived â-ketoester
1a as nucleophile and allenic ester 3a as electrophile, several
mild inorganic bases gave high conversion to the desired â,γ-
unsaturated carbonyl compound at -20 °C. After optimization,
it turned out that K2CO3 was the base of choice in terms of
conversion and enantioselectivity (see Supporting Information).
Using liquid-liquid phase-transfer conditions with aq K2CO3
as the base at -20 °C afforded the conjugate addition product
4a after 18 h reaction time with full conversion and a high
enantioselectivity using only 1.3 equiv of allene 3a and 3 mol
% of catalyst.
Chart 2. Steric Interactions Favoring Formation of (E)-Products
with 4-Substituted Activated Allenes
After identification of the best conditions for the catalytic
enantioselective conjugate addition to activated allenes, we
tested different allenes 3a-e using 1-indanone-derived â-ke-
toester 1a as a model substrate employing 3 mol % of catalyst
6. As summarized in Table 1, allenes with an ester or a ketone
moiety as activating group afforded the corresponding â,γ-
Having in hand a general and efficient protocol for the
asymmetric conjugate addition to activated allenes, we next
explored to which extent this catalytic system could be applied
to various other cyclic â-ketoesters. As can be seen from Table
2, different cyclic â-ketoesters 1b-h were found to be suitable
for this catalytic transformation, providing addition products
4f-o generally in good to excellent yields (59-95%) and
enantioselectivities (67-95% ee).
(22) For reviews on the use of 2 for asymmetric transformations under PTC,
see: (a) O’Donnell, M. J. Aldrichim. Acta 2001, 34, 3. (b) Maruoka, K.;
Ooi, T. Chem. ReV. 2003, 103, 3013. (c) O’Donnell, M. J. Acc. Chem.
Res. 2004, 37, 506. (d) Lygo, B.; Andrews, B. I. Acc. Chem. Res. 2004,
37, 518. (e) Ooi, T.; Maruoka, K. Angew. Chem., Int. Ed. 2007, 46, 4222.
(f) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 2007,
18, 569.
(23) (a) Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595. (b) Corey,
E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. (c) Corey,
E. J.; Noe, M. C. Org. Synth. 2003, 80, 38.
As expected, the catalytic system had to be fine tuned for
some â-ketoesters through variation of the inorganic base. While
the 1-indanone-derived â-ketoester 1b bearing electron-donating
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Table 1. Catalytic Asymmetric Conjugate Addition of â-KetoesterssVariation of the Allenea
a Reaction performed with 0.20 mmol of 1a (0.16 M), 0.6 mL of aq base, 0.26 mmol of allene 3, and 3 mol % of catalyst 6. Values in parentheses refer
to the opposite enantiomer, obtained using catalyst 6′. b Isolated yield after column chromatography. c The enantiomeric excess was determined by HPLC
using an amylose-tris-(3,5-dimethylphenylcarbamate) column (Daicel Chiralpak AD) or a cellulose-tris-(3,5-dimethylphenylcarbamate) column (Daicel Chiralcel
OD). d Major diastereomer determined as E-isomer in analogy to compound 4h. e 50 wt % aq K2HPO4 was used as the base.
groups at the aromatic ring worked well with the initially
established conditions (entry 1), the â-ketoester 1c with a
5-chloro-substituent gave only 58% ee with K2CO3 as a base.
However, changing to the milder base K2HPO4 gave adduct 4g
with an increased enantioselectivity of 90% ee (entry 2).
Recrystallization from hexane afforded the product in enantio-
merically pure form. The lowest enantioselectivy was obtained
with 2-indanone-derived â-ketoester 1d (entry 4). It turned out
that the substrate 1d underwent decarboxylation during the
course of the reaction, giving 2-indanone as a byproduct. In
order to lower the reaction times, stronger inorganic bases were
tested which resulted in higher yields of the desired adduct 4i
but unfortunately also in decreased enantioselectivity (see
Supporting Information). Finally, we used an increased catalyst
loading of 6 mol % and 3 equiv of allene in combination with
an aqueous saturated NaHCO3 solution as basic media to obtain
the best combination of chemical yield and enantioselectivity.
In contrast, the least reactive â-ketoesters 1e,g,h based on the
cyclohexanone core gave very good results when stronger bases
were applied. The most reactive among these, â-ketoester 1e,
afforded the corresponding adduct 4j even with aq Cs2CO3 as
a base and 3 mol % of catalyst 6 in excellent yield and
enantioselectivity (entry 5). This reaction was additionally scaled
up to 8.1 mmol of substrate, and full conversion and product
4j was obtained in 85% yield (2.48 g) after column chroma-
tography with an enantiomeric excess of 96% ee. In the case of
â-ketoesters 1g and 1h it turned out that the addition products
could be formed with satisfactory yields switching to aq K3-
PO4 as a base in combination with a slightly increased
temperature and catalyst loading (entries 8 and 10). When
scaling up the reaction with â-ketoester 1g and allene 3a to 7.5
mmol of substrate it turned out that the conversion stopped at
70% after 96 h. However, 4m was isolated in 53% yield (1.23
g) after column chromatography, and the high enantiomeric
excess of 91% ee was retained. When conducting the reaction
of â-ketoester 1g with acetylallene 3b as electrophile it was
necessary to switch to solid-liquid phase-transfer conditions
(Cs2CO3, 1.2 equiv) and lower the temperature in order to
suppress partial olefin isomerization of the formed product (entry
9, for details see Supporting Information). Finally, for cyclo-
pentane-derived â-ketoester 1f we investigated whether an
increase of the bulk at the ester moiety of the allene had an
impact on the enantioselectivity, since the reaction with ethyl
allenoate 3a furnished the product 4k in only moderate
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Table 2. Catalytic Asymmetric Conjugate Addition of â-KetoesterssVariation of the â-Ketoestera
a Reactions performed with 0.20 mmol of 1 (0.16 M in o-xylene/CHCl3 7:1), 0.6 mL of aqueous base (concentrations are given in wt%), 0.26 mmol of
allene 3, and 3 mol % of 6. b Isolated yields after column chromatography. c The enantiomeric excess was determined by HPLC using an amylose-tris-
(3,5-dimethylphenylcarbamate) column (Daicel Chiralpak AD), a cellulose-tris-(3,5-dimethylphenylcarbamate) column (Daicel Chiralcel OD), a cellulose-
tris-(4-methylbenzoate) column (Daicel Chiralcel OJ) or GC. d After recrystallization from hexane. e Reaction performed on a 1.13 mmol scale. f 6 mol %
g
1
of catalyst 6 was used. 0.60 mmol of allene 3 was used. h The E/Z ratio was determined as 9:1 by H NMR. i 0.24 mmol of solid base was used.
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enantioselectivity (entry 6). As can be seen from entry 7, a
switch to tert-butyl allenoate 3f as electrophile gave no
significant improvement in enantioselectivity.
of the double bond to furnish the two diastereomeric lactones
10a and 10b in a ratio of 2:1 separable by column chromatog-
raphy (Scheme 3). The use of LiClO4 or CeCl3‚7H2O as additive
gave only minor results in terms of yield and diastereoselectivity.
In the latter case a complex mixture was obtained containing
also the diastereomeric diols formed by reduction of both the
keto and the ethyl ester group.
On the basis of NMR and X-ray analysis, the relative
configurations were assigned as cis for lactone 10a and trans
for lactone 10b. Comparison of the 1H NMR spectra of lactones
10a and 10b showed a significant downfield shift for the proton
at the ring junction in lactone 10a, indicating enhanced shielding
of this proton by the ester group. This is in good agreement
with former observations for very similar bicyclic lactones with
an ester group at the ring junction.28 This assignment was finally
confirmed by the X-ray structure of lactone 10a (Chart 4), which
The absolute configuration of compound 4g was determined
to be S by X-ray crystallography (Chart 3).24 The observed
absolute configuration is accounted for by shielding of the Re
face of the enolate formed from â-ketoesters 1 via deprotonation
by catalyst 6, which is in agreement with our proposed model
of a defined tight ion pair between the chiral quaternary
ammonium salt 6 and the enolates derived from tert-butyl
â-ketoesters 1.25
Chart 3. X-ray Crystal Structure of Compound 4ga
Chart 4. X-ray Crystal Structure of Compound 10aa
a C, gray; H, white; O, red; Cl, green.
The products arising from this catalytic process bearing a
quaternary chiral center, an exo-double bond, and various
carbonyl functionalities possess, in general, a high potential for
further synthetic transformations. For example, in light of several
classes of natural compounds comprising the hexahydroben-
zopyranone core26 as well as total synthesis based on that
motif,27 cyclohexanone derivative 4m seemed to be for us a
promising starting point to gain rapid access to this kind of chiral
bicyclic building block. After a short investigation, it turned
out that we were able to meet our objectives by treatment of
4m with NaBH4 in the presence of stoichiometric amounts of
anhydrous CaCl2. Under these reaction conditions, the keto
group was reduced chemoselectively and the resulting alcohol
underwent subsequent lactonization followed by isomerization
a C, gray; H, white; O, red.
was obtained with an enhanced enantiomeric excess of >98%
ee after recrystallization from pentane.24
Schiff Bases Derived from R-Amino Acids as Nucleophiles.
Despite the many and, in principle, general methods available
for synthetic access of chiral R-branched amino acids,22f,29 there
is ongoing interest and research in this field considering the
development of general and efficient strategies. In the late 1970s
O’Donnell and co-workers introduced the stable Schiff bases 2
derived from glycine esters and benzophenone as suitable
nucleophiles for the synthesis of optically active R-alkylated
amino acids under phase-transfer conditions.30 Since then
Scheme 3 . Synthesis of Hexahydrobenzopyranone Derivatives 10a and 10b
9
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Conjugate Addition to Allenic Esters and Ketones
A R T I C L E S
application of chiral phase-transfer catalysts has had a major
impact on the synthesis of optically active natural and unnatural
R-amino acids. In particular, the use of quaternary ammonium
salts derived from cinchona alkaloids has been studied thor-
oughly, culminating in the development of N-(9-anthracenyl-
methyl)ammonium salts of cinchonine and cinchonidine show-
ing high enantioselectivities for alkylation of imine 2a.22
Moreover, it was shown that the scope of this catalytic system
could be extended to 1,4-addition reactions with R,â-unsaturated
carbonyl compounds31 and 1,6-addition reactions with activated
dienes,21j respectively. Another highly suitable catalyst (9, Chart
5) based on a biphenyl backbone was introduced by Lygo et
al. to perform conjugate addition reactions of 2b to methyl vinyl
ketones.32 However, preparation of this catalyst requires six
synthetic steps. Considering the commercial availability of
catalyst 8 and easy access of catalyst 7 which was shown to be
as effective as catalyst 8 for the asymmetric alkylation of 2a,33
we decided to focus first on these cinchona alkaloid-based
catalysts in order to promote an asymmetric conjugate addition
of benzophenone imine 2a to allene 3a (Table 3).34 In contrast
to the countless methods able to provide enantioenriched
R-alkyl-substituted R-amino acid derivatives with high fidelity
through alkylation of 2a, addition of the same imine to allenes
has, to our knowledge, never been reported in an asymmetric
fashion, although this transformation certainly represents direct
access to optically active R-vinyl-substituted R-amino acid
derivatives.
that full conversion to the desired product 5a could only be
obtained using solid CsOH‚H2O as a base. Performing the
reaction at -40 °C in CH2Cl2 with 3.0 equiv of allenoate 3a
seemed to be the optimum conditions to get a high turnover
rate and full conversion to the desired product 5a. A high
turnover rate was found to be crucial to obtain the best
enantioselectivities, since elevated reaction times lead to a
decrease in the enantioselectivity. This supported the initial
consideration of product 5a being prone to undergo racemization
under these reaction conditions.
Having set the parameters in terms of conversion, we
compared the cinchonidine-derived catalysts 7 and 8 under these
reactions conditions. As can be seen from Table 3, catalyst 7
furnished compound 5a in almost racemic form (entry 1) and
catalyst 8 showed a moderate enantioselectivity of 60% ee (entry
2). Lowering the temperature (entry 3) had no influence on the
enantioselectivity, and using toluene as a cosolvent (entry 4)
gave only a slight increase in enantioselectivity. In order to test
if another catalyst was able to improve the enantioselectivity,
we applied chiral ammonium salt 9 to the before optimized
conditions. Performing the reaction with only 1 mol % of
catalyst 9 gave full conversion to the product 5a after 2 h;
however, the enantioselectivity dropped to 15% ee (entry 5).
Inspired by the work of Lygo et al.,32 we next tried Et2O as a
solvent together with a higher dilution of the reaction mixture
due to solubility reasons. In this case, longer reaction times were
needed to reach full conversion to the desired product 5a. To
our delight, the enantioselectivity increased to 58% ee using
CsOH‚H2O as the base at -40 °C and to 63% ee using
Cs2CO3 as the base at 4 °C. Being able to reach full conver-
sion with the use of a mild base such as Cs2CO3 encouraged us
to apply this catalytic system for optimization. Finally, by
increasing the catalyst loading to 4 mol % and using the
sterically more demanding benzophenone imine 2b we were
able to obtain the corresponding imino ester 5b after 4 h at 4
°C with full conversion and a high enantioselectivity of 86%
ee (entry 8).35
Chart 5
The two optimized systems for application of catalysts 8 and
9 in the addition of glycine imines 2a and 2b to allenic ester
3a were subsequently scaled up to give products 5a and 5b in
high yields and reproducibly moderate enantioselectivity for 5a
(Table 4, entry 1) and high enantioselectivity for 5b (Table 4,
entry 2). This reaction was also scaled up, and compound 5b
was obtained in 80% yield (1.26 g) after 5.5 h of reaction time
and an enantiomeric excess of 85% ee when performing the
reaction on a 3.0 mmol scale with respect to substrate 2b.
Glycine imine 2b was also successfully added to allenic
ketone 3b. The corresponding product 5c was isolated in 62%
yield and showed a high enantioselectivity of 88% ee (Table 4,
entry 3).
At the outset we had to consider both the fragility of the
electrophile as well as the formed product toward basic
conditions, so we first tried to evade the strongly basic
conditions usually required to obtain reasonable conversion with
benzophenone imine 2a. After testing several bases, tempera-
tures, and solvents (see Supporting Information) it turned out
(24) The crystallographic coordinates of 4g (CCDC 654132) as well as 10a
(CCDC 664412) have been deposited with the Cambridge Crystallographic
Data Centre. These data can be obtained free of charge from the the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(25) This model was developed on the basis of an X-ray analysis of catalyst 6
bearing p-nitrophenolate as the counterion. See ref 21i.
(26) (a) Shing, T. K. M.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2005, 44, 7981.
(b) Murakami, N.; Sugimoto, M.; Kawanishi, M.; Tamura, S.; Kim, H.-S.;
Begum, K.; Wataya, Y.; Kobayashi, M. J. Med. Chem. 2003, 46, 638.
(27) Ahmad, Z.; Ray, U. K.; Venkateswaran, R. V. Tetrahedron 1990, 46, 957.
(28) (a) Krawczyk, H.; SÄliwin´ski, M. Tetrahedron 2003, 59, 9199. (b) SÄliwin´ski,
M.; Wojciech, M. W.; Bodalski, R. Synlett 2004, 11, 1995.
(29) For a recent reviews on catalytic asymmetric synthesis of R-amino acids,
see: Na´jera, C.; Sansano, J. M. Chem. ReV. 2007, 107, 4584.
(30) O’Donnell, M. J.; Boniece, J. M.; Earp, S. E. Tetrahedron Lett. 1978, 19,
2641.
The general synthetic utility of the R-vinylated imino esters
5 was demonstrated by their straightforward transformation into
(32) Lygo, B.; Allbutt, B.; Kirton, E. H. M. Tetrahedron Lett. 2005, 46, 4461.
(33) Jew, S.-S.; Yoo, M.-S.; Jeong, B.-S.; Park, H.-G. Org. Lett. 2002, 4, 4245.
(34) It should be noted that 6 and 6′ are less effective catalysts compared to 8,
giving the catalytic product in very low yield. In the solid state a
p-nitrophenolate counterion in catalyst 6 was found to be in a different
position with respect to the quaternary nitrogen atom, compared to the same
counterion in catalyst 8, presumably due to the steric effects exerted by
the 1-adamantoyl substituent. For a discussion, see ref 21i.
(31) (a) Corey, E. J.; Noe, M. C.; Xu, F. Tetrahedron Lett. 1998, 39, 5347. (b)
Chinchilla, R.; Mazo´n, P.; Na´jera, C.; Ortega, F. J.; Yus, M. ArkiVoc 2005,
Vi, 222.
(35) It has to be noted that the more bulky glycine imine 2b has an opposite
effect on the enantioselectivity with catalyst 8 giving the product 5b with
only 35% ee.
9
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A R T I C L E S
Elsner et al.
Table 3. Catalytic Asymmetric Conjugate Addition of Glycine Imines 2sOptimization of Reaction Conditionsa
a Reaction performed with 0.05 mmol of 2a or 2b (0.16 M), 0.25 mmol of solid base, 0.15 mmol of allene 3a, and 5 mol % of catalyst. b Determined by
1H NMR spectroscopy. c Determined by chiral stationary phase HPLC using an amylose-tris-(3,5-dimethylphenylcarbamate) column (Daicel Chiralpak AD).
Compound 5a was transformed into the corresponding Cbz-protected amino ester before HPLC analysis (see Supporting Information). d 1 mol % of catalyst
9 was used. e 4 mol % of catalyst 9 was used. f Concentration was 0.05 M. g The opposite enantiomer was enriched.
Scheme 4 . Synthesis of 2,3-Disubstituted γ-Lactames 11
This transformation exemplifies that direct access to optically
active substituted γ-lactames from the R-vinylated imino ester
5b is in general possible. The γ-lactam core displays a unique
structural motif for a variety of biologically active molecules.
Among these, Lactacystin and Salinosporamide A have currently
attracted a lot of attention due to their potent biological
properties and synthetically challenging structure.36 Furthermore,
2,3-disubstituted γ-lactames are useful scaffolds for the synthesis
of halipeptins37 as well as peptide mimetics.38
Conclusion
In this article the first example of a catalytic asymmetric
conjugate addition to electron-deficient allenes to form tertiary
and quaternary stereogenic centers has been described. The
reaction enables the R-vinylation of cyclic â-ketoesters using a
readily accessible cinchona-alkaloid-derived chiral phase-transfer
catalyst under experimentally simple conditions. The products
are isolated generally in high yields and with excellent diastereo-
the corresponding 2,3-disubstituted γ-lactames 11. This con-
secutive three-step transformation outlined in Scheme 4 included
homogeneous hydrogenation of the double bond with Wilkin-
son’s catalyst followed by transesterification of the two ester
groups and subsequent hydrolysis/cyclization with aq AcOH.
It should be noted that attempts to cyclize imino ester 5b directly
with aq AcOH led to considerable racemization, and the
corresponding unsaturated lactam was obtained with an enan-
tioselectivity of 18% ee. The assignment of relative stereo-
chemistry of lactames 11a and 11b was made by comparison
of their NMR data with literature data (see Supporting Informa-
tion).
(36) For a review, see: Shibasaki, M.; Kanai, M.; Fukuda, N. Chem. Asian J.
2007, 2, 20.
(37) Hara, S.; Makino, K.; Hamada, Y. Tetrahedron 2004, 60, 8031.
(38) (a) Hannessian, S.; Yun, H.; Hou, Y.; Tintelnot-Blomely, M. J. Org. Chem.
2005, 70, 6746. (b) Zhang, J.; Ying, J.; Wang, W.; Hruby, V. J. Org. Lett.
2003, 5, 3115. (c) Bentz, E. L.; Goswami, R.; Moloney, M. G.; Westaway,
S. M. Org. Biomol. Chem. 2005, 3, 2872.
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4904 J. AM. CHEM. SOC. VOL. 130, NO. 14, 2008

Conjugate Addition to Allenic Esters and Ketones
A R T I C L E S
Table 4. Catalytic Asymmetric Conjugate Addition of Glycine Imines 2a
a Conditions A: Reaction performed with 0.2 mmol of 2a (0.16 M), 1.0 mmol of CsOH·H2O, 0.6 mmol of allene 3a, and 5 mol % of catalyst 8 at -40 °C
in toluene/CH2Cl2 (2:1). Conditions B: Reaction performed with 0.2 mmol of 2b (0.05 M), 1.0 mmol of Cs2CO3, 0.6 mmol of allene 3a or 3b, and 4 mol
% of catalyst 9 at 4 °C in Et2O. b Isolated yield after column chromatography. c Determined by chiral stationary phase HPLC using an amylose-tris-(3,5-
dimethylphenylcarbamate) column (Daicel Chiralpak AD). d Enantiomeric excess determined after transformation of 5a into the corresponding Cbz-protected
amino ester 5d (see Supporting Information).
and enantioselectivities. The reaction exhibits broad substrate
scope in both the cyclic â-ketoester as well as the allenic moiety.
Furthermore, it was shown that R-vinylation of glycine imine
derivatives can be achieved with high enantioselectivities,
changing to chiral phase-transfer catalyst based on a substituted
procedures and characterizations (PDF). This information is
biphenyl backbone. Finally, the synthetic value of the chiral
products arising from this catalytic process was exemplified by
Acknowledgment. This work was made possible by a grant
from The Danish National Research Foundation and OChem
School.
Supporting Information Available: Complete experimental
available free of charge via the Internet at http://pubs.acs.org.
their straightforward transformation into optically active hexahy-
drobenzopyranones and γ-lactames, respectively.
JA710689C
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