Acyl Phosphonates: Good hydrogen bond acceptors and ester/amide equivalents in asymmetric organocatalysis

Article abstract of DOI:10.1021/ja9097803

This study demonstrates that unsaturated acyl phosphonates are excellent hydrogen-bond acceptors in enantioselective organocatalysis. By employing chiral thioureas orsquaramides as catalysts, the acyl phosphonates are effectively coordinated and activated

Full text of DOI:10.1021/ja9097803

Published on Web 02/04/2010
Acyl Phosphonates: Good Hydrogen Bond Acceptors and
Ester/Amide Equivalents in Asymmetric Organocatalysis
Hao Jiang, Ma´rcio W. Paixa˜o, David Monge, and Karl Anker Jørgensen*
Center for Catalysis, Department of Chemistry, Aarhus UniVersity,
DK-8000 Aarhus C, Denmark
Received November 25, 2009; E-mail: kaj@chem.au.dk
Abstract: This study demonstrates that unsaturated acyl phosphonates are excellent hydrogen-bond
acceptors in enantioselective organocatalysis. By employing chiral thioureas or squaramides as catalysts,
the acyl phosphonates are effectively coordinated and activated by hydrogen bonding, thereby providing
successful relay of the chirality from the catalyst to the substrate. A variety of highly stereoselective conjugate
additions to R,ꢀ-unsaturated acyl phosphonates were performed, using different carbon-based nucleophiles
such as oxazolones, indoles, and 1,3-dicarbonyl compounds. The reaction concept has been developed
to be a double nucleophilic reaction, and it is shown that the acyl phosphonates serve as masked ester or
amide equivalents, which upon quenching with the second nucleophile generate the parent structures in
situ. Accordingly, formal C-C bond formation reactions of ester and amide substrates are achieved, affording
a broad spectrum of optically active conjugate adducts in good yields and excellent enantioselectivities.
Based on the experimental results, the mechanisms for the different reactions are discussed, including the
approach of the oxazolones, indoles, and 1,3-dicarbonyl compounds to the acyl phosphonate coordinated
to the catalyst and the role of the catalyst for the reaction course of the nucleophiles.
Introduction
to possess certain qualities: (i) enhanced activation of the
substrate toward nucleophilic attack; (ii) improved coordination
Enantioselective nucleophilic addition to electron-poor alk-
enes is a fundamental transformation in asymmetric synthesis.
Nowadays, rapid advances in asymmetric catalysis have gener-
ated a broad scope of effective methods for ꢀ-functionalization
of various Michael acceptors such as enals, enones, nitro
alkenes, and vinyl sulfones.1 Interestingly, activation and chiral
induction of simple conjugated esters or amides remains a
challenging task, with fewer successful reports. Especially
simple alkenyl esters have proven to be difficult substrates for
effective chirality relay in asymmetric catalysis. An in-direct,
but equally efficient, strategy to encounter this problem is the
use of activated ester surrogates as masked equivalents of the
desired products. A nucleophile is first added in a stereoselective
manner to the unsaturated ester surrogates, and upon completion
of reaction, a second nucleophile is employed for a subsequent
acyl substitution reaction, furnishing the overall formal ester
functionalization reaction by a double nucleophilic addition
sequence. Attractive ester and amide surrogates are expected
to the chiral catalyst; (iii) easy and mild replacement upon
demand and preferably in a one-pot fashion (Scheme 1). Despite
the extensive research in activated ester equivalents, only few
truly meet all three criteria. Examples of successful cases
includes the use of unsaturated activated imides, 2-acyl imid-
azoles, styrylisoxazoles, or N-acylpyrroles, which have been
employed in the described stereoselective double nucleophilic
reactions using organometallic catalysis or organocatalysis.2
Acyl phosphonates were introduced as activated ester sur-
rogates in asymmetric catalysis by Evans et al.3 Because of the
(2) For selected examples, see. (a) Evans, D. A.; Johnson, J. S.; Olhava,
E. J. J. Am. Chem. Soc. 2000, 122, 2035. (b) Evans, D. A.; Fandrick,
K. R.; Song, H.-J.; Scheidt, K. A.; Xu, R. J. Am. Chem. Soc. 2007,
129, 10029. (c) Sibi, M. P.; Itoh, K. J. Am. Chem. Soc. 2007, 129,
8064. (d) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121,
8959. (e) Guerin, D. J.; Miller, S. J. J. Am. Chem. Soc. 2002, 124,
2134. (f) Balskus, E. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2006,
128, 6810. (g) Vanderwal, C. D.; Jacobsen, E. N. J. Am. Chem. Soc.
2004, 126, 14724. (h) Matsunaga, S.; Kinoshita, T.; Okada, S.; Harada,
S.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 7559. (i) Evans, D. A.;
Scheidt, K. A.; Johnston, J. N.; Willis, M. C. J. Am. Chem. Soc. 2001,
123, 4480. (j) Sibi, M. P.; Manyem, S.; Zimmerman, J. Chem. ReV.
2003, 103, 3263, and references therein. (k) Zhuang, W.; Hazell, R. G.;
Jørgensen, K. A. Chem. Commun. 2001, 1240. (l) Kobayashi, S.;
Ogawa, C.; Kawamura, M.; Sugiura, M. Synlett 2001, 983. (m) Hird,
A. W.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2003, 42, 1276. (n)
Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394. (o) Sibi,
M. P.; Ma, Z.-H.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126, 718.
(p) Coquiere, D.; Feringa, B. L.; Roelfes, G. Angew. Chem., Int. Ed.
2007, 46, 9308. (q) Evans, D. A.; Fandrick, K. R.; Song, H.-J. J. Am.
Chem. Soc. 2005, 127, 8942. (r) Baschieri, A.; Bernardi, L.; Ricci,
A.; Suresh, S.; Adamo, M. P. A. Angew. Chem., Int. Ed. 2009, 48,
9342. (s) Hoashi, Y.; Okino, T.; Takemoto, Y. Angew. Chem., Int.
Ed. 2005, 44, 4032. (t) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am.
Chem. Soc. 2006, 128, 9413. See also ref 11d.
(1) For recent reviews on asymmetric conjugate addition, see. (a) Rossiter,
B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771. (b) Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033. (c) Krause, N.; Hoffmann-
Ro¨der, A. Synthesis 2001, 171. For reviews on metal-catalyzed
asymmetric conjugate addition, see (d) Alexakis, A.; Ba¨ckvall, J.-E.;
Krause, N.; Pa`mies, O.; Die´guez, M. Chem. ReV. 2008, 108, 2796.
(e) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard, A. J.;
Feringa, B. L. Chem. ReV. 2008, 108, 2824. (f) Alexakis, A.; Benhaim,
C. Eur. J. Org. Chem. 2002, 3221. (g) Christoffers, J.; Koripelly, G.;
Rosiak, A.; Ro¨ssle, M. Synthesis 2007, 1279. For reviews on
organocatalytic asymmetric conjugate additions, see (h) Vicario, J. L.;
Badia, D.; Carrillo, L. Synthesis 2007, 2065. (i) Tsogoeva, S. B. Eur.
J. Org. Chem. 2007, 1701. (j) Almasi, D.; Alonso, D. A.; Najera, C.
Tetrahedron: Asymmetry 2007, 18, 299. (k) Enders, D.; Wang, C.;
Liebich, J. X. Chem.sEur. J. 2009, 15, 11058, and references therein.
9
10.1021/ja9097803  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 2775–2783 2775

A R T I C L E S
Jiang et al.
Scheme 1. Formal ꢀ-Funtionalizations of Esters and Amides Using Activated Ester Surrogates
Scheme 2. Acyl Phosphonates and Methods of Activation
observed lability of the C-P bond, they serve as effective acyl
donors, enabling simple transformation to the parent ester or
amide motif. The adjacent CdO and PdO groups are generally
positioned with a dihedral angle of 180° as result of dipole
effects; however, reorientation in the presence of favorable
interactions is possible, as demonstrated by Breuer et al., who
calculated the energy difference between s-trans and s-cis
conformation of the C-P bond of dimethyl benzoylphosphonate
to be only 1.8 kcal.3i In their study, Evans et al. have
demonstrated that chelation of chiral metal complexes to R,ꢀ-
unsaturated acyl phosphonates is possible, enabling their ap-
plication in enantioselective conjugate additions and hetero
Diels-Alder reactions.3a-c Foreshadowed by this work, an
alternative activation strategy was pursued.
ꢀ-substituted esters and amides that may serve as chiral building
blocks in asymmetric synthesis.
Results and Discussion
Oxazolone Additions. The chemistry of oxazol-5-(4H)-ones
(referred to as oxazolones in the remaining text) dates more
than a century previous, when Plo¨chl et al. in 1883 described
the first synthesis via a condensation reaction of benzaldehyde
and hippuric acid in presence of acetic anhydride.6 For a period
of time, the structure of penicillin was incorrectly thought to
be an oxazolone, leading to increased interest in this class of
compound in the 1940s.7 The chemistry of oxazolones was later
extensively explored, revealing multiple reactivity patterns,
including nucleo- and electrophilic pathways. Serving as a
general and flexible structural skeleton, oxazolones are an
excellent template for diversity-oriented syntheses of important
and relevant products, such as amino acids and versatile
heterocyclic structures.8
Nucleophilic addition of oxazolones takes place to either the
C-2 or C-4 carbon atoms, affording in both cases a quaternary
stereogenic center. As outlined in Scheme 3, regioselective
addition of oxazolones to electrophiles such as acyl phospho-
nates may afford two possible addition adducts A or B. From
C-2 addition, a rare class of optically active quaternary
In the following, we will demonstrate that by application of
a strong hydrogen(H)-bond donor, such as a chiral thiourea,
the acyl phosphonate motif can be effectively coordinated and
activated, enabling formal ꢀ-functionalizations of esters and
amides using enantioselective H-bonding catalysis (Scheme 2).4
Herein, we report our investigations in the use of acyl
phosphonates as H-bond acceptors in enantioselective organo-
catalysis.5 Important carbon-based nucleophiles such as oxazol-
ones, indoles, and cyclic 1,3-dicarbonyl compounds were
successfully introduced with good yields and excellent enantio-
and diastereoselectivities using small molecule chiral H-donors
as catalysts. This new approach permits an easy and straight-
forward route to a range of highly potent optically active
(5) For recent general reviews on organocatalysis, see: (a) MacMillan,
D. W. C. Nature 2008, 455, 304. (b) Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2007, 47, 42. For selected reviews on amino-catalysis, see
(c) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem.,
Int. Ed. 2008, 47, 6138. (d) Mielgo, A.; Palomo, C. Chem. Asian J.
2008, 3, 922. (e) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008,
47, 4638. (f) Erkkila, A.; Majander, I.; Pihko, P. M. Chem. ReV. 2007,
107, 5416. (g) List, B. Chem. Commun. 2006, 819. For reviews on
H-bonding catalysis, see ref 4.
(3) (a) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc. 1998, 120, 4895.
(b) Evans, D. A.; Johnson, J. S.; Burgey, C. S.; Campos, K. R.
Tetrahedron Lett. 1999, 40, 2879. (c) Evans, D. A.; Scheidt, K. A.;
Fandrick, K. R.; Lam, H. W.; Wu, J. J. Am. Chem. Soc. 2003, 125,
10780. (d) Takenaka, N.; Abell, J. P.; Yamamoto, H. J. Am. Chem.
Soc. 2007, 129, 742. (e) Samanta, S.; Zhao, C.-G. J. Am. Chem. Soc.
2006, 128, 7442. (f) Samanta, S.; Krause, J.; Mandai, T.; Zhao, C.-G.
Org. Lett. 2007, 9, 2745. For application in racemic synthesis, see (g)
Hanessian, S.; Compain, P. Tetrahedron 2002, 58, 6521. (h) Telan,
L. A.; Poon, C.-D.; Evans, S. A. J. Org. Chem. 1996, 61, 7455. For
theoretical calculations, see (i) Karaman, R.; Goldblum, A.; Breuer,
E.; Leader, H. J. Chem. Soc., Perkin Trans. 1 1989, 765.
(6) Plo¨chl, J. Ber. Dtsch. Chem. Ges. 1900, 33, 2815.
(7) Clarke, H. T.; Johnson, J. R.; Robinson, R. In Oxazoles and
Oxazolones; Princeton University Press: Princeton, NJ, 1949; pp 688-
848.
(8) For recent review, see. (a) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem.
Soc. ReV. 2007, 36, 1432. For application of oxazolones in organo-
catalysis, see (b) Ale´man, J.; Milelli, A.; Cabrera, S.; Reyes, E.;
Jørgensen, K. A. Chem.sEur. J. 2008, 14, 10958. (c) Cabrera, S.;
Reyes, E.; Ale´man, J.; Milelli, A.; Kobbelgaard, S.; Jørgensen, K. A.
J. Am. Chem. Soc. 2008, 130, 12031. (d) Uraguchi, D.; Asai, Y.; Ooi,
T. Angew. Chem., Int. Ed. 2009, 48, 733. (e) Berkessel, A.; Cleemann,
F.; Mukherjee, S.; Mu¨ller, T. N.; Lex, J. Angew. Chem., Int. Ed. 2005,
44, 807. (f) Lee, J. W.; Ryu, T. H.; Oh, J. K.; Bae, H. Y.; Jang, H. B.;
Song, C. E. Chem. Commun. 2009, 7224. (g) Balaguer, A.-N.;
Company´o, X.; Calvet, T.; Font-Bard´ıa, M.; Moyano, A.; Rios, R.
Eur. J. Org. Chem. 2009, 199. For addition of oxazolones to ester
surrogates, see (h) Uraguchi, D.; Ueki, Y.; Ooi, T. Science 2009, 326,
120.
(4) For recent reviews, see. (a) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV.
Synth. Catal. 2006, 348, 999. (b) Connon, S. J. Chem.sEur. J. 2006,
12, 5418. (c) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2006, 45, 1520. (d) Doyle, A. G.; Jacobsen, E. N. Chem. ReV. 2007,
107, 5713. (e) Takemoto, Y.; Miyabe, H. Chimia 2007, 61, 269. (f)
Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516, and references
thereinFor the seminal paper, see (g) Sigman, M. S.; Jacobsen, E. N.
J. Am. Chem. Soc. 1998, 120, 4901. For computational studies, see
(h) Schreiner, P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217.
9
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Acyl Phosphonates
A R T I C L E S
Figure 1. The influence of catalyst and substituents on regioselectivity.
N,O-acetals,8h,9 with two continuous stereocenters, is obtained.
Alternatively, if the reaction occurs at the C-4 carbon atom,
forming the addition adduct B, a range of masked R,R-
disubstituted amino acids10 is accessible. Because of the
synthetic relevance of both classes of compounds, control of
reaction pathways is highly desired. Initial observations led us
to believe that the issue of regioselectivity can be addressed by
proper selection of substituents and catalyst.
The methyl ester product 4a is formed as a single diastereomer
in 72% and 82% ee, respectively (entries 1, 2). The use of
halogenated solvents such as CH2Cl2 and CF3C6H5 led to slight
erosion of yield and enantioselectivity (entries 3, 4). A lowering
of the temperature to -40 °C or variation in the stoichiometry
of the reaction partners had limited effect on the outcome of
the reaction (entries 5, 6). However, further dilution of the
reaction mixture ([1a] ) 0.2 M) led to an increase in enantio-
selectivity, furnishing the product 4a in 67% yield and 90% ee
(entry 8).
Scheme 3. Regioselectivity of Nucleophilic Oxazolone Additions to
Electrophiles
Table 1. Screening Results of C-2 Selective Addition of
2-(2-Chlorophenyl)-4-isobutyloxazol-5(4H)-one 2a to (E)-Dimethyl
But-2-enoylphosphonate 1aa
We envisioned that a bifunctional thiourea catalyst with a
basic site might deprotonate the oxazolone prior to addition,
revealing an oxazole enolate species, where both the C-2 and
the C-4 position are activated (Figure 1, right). In such a case,
the electronic nature of the side chains on the oxazolones ring
(R2 and R3) should have decisive influence on the reaction
course. Alternatively, omission of the basic site or exchange
for an additional hydrogen-donor group on the catalyst (Figure
1, left) would lead to nucleophilic attack primarily at the C-4
center.
entry
catalyst
[1a] (M)
solvent
T (°C)
yield (%)b
ee (%)c
For the reaction of acyl phosphonates with oxazolones, we
started our screening with the cinchona alkaloid-based thiourea
catalysts 3a,b11 (Table 1) because they are easily available in
multigram quantities. 2-(2-Chlorophenyl)-4-isobutyloxazol-
5(4H)-one 2a with an electron-deficient aromatic ring attached
to C-2 and an alkyl chain at C-4 was identified as a good
candidate to promote the selective C-2 conjugate addition. The
reaction of (E)-dimethyl but-2-enoylphosphonate 1a with 2a in
the presence of catalyst 3a or 3b in toluene as solvent at -20
°C afforded exclusively the desired C-2 addition product 4a
upon quenching with DBU and a second nucleophile (MeOH).
1
2
3
4
5
6
7
8
3a
3b
3b
3b
3b
3b
3b
3b
1.0
1.0
1.0
1.0
1.0d
1.0
0.33
0.2
toluene
toluene
CH2Cl2
CF3C6H5
toluene
toluene
toluene
toluene
-20
-20
-20
-20
-20
-40
-20
-20
37
62
34
41
53
62
50
67
-72
82
74
72
82
83
89
90
a Unless otherwise stated, 0.1 mmol of 1a, 0.3 mmol of 2a and 0.01
mmol of 3 were reacted at the given temperature for 24-48 h. b Isolated
yields. c Determined by chiral stationary phase HPLC. d 1a (0.3 mmol)
and 2a (0.1 mmol) were employed. [2a] ) 1 M.
(9) For racemic synthesis of N,O-acetals, see. (a) Harayama, Y.; Yoshida,
M.; Kamimura, D.; Wada, Y.; Kita, Y. Chem.sEur. J. 2006, 12, 4893,
and references hereinFor chiral synthesis starting from enantiopure
compounds, see (b) Seebach, D.; Aebi, J. D. Tetrahedron Lett. 1984,
25, 2545. (c) Seebach, D.; Aebi, J. D.; Gander-Coquoz, M.; Naef, R.
HelV. Chim. Acta 1987, 70, 1194. (d) Brunner, M.; Straub, T.;
Saarenketo, P.; Rissanen, K.; Koskinen, A. M. P. Lett. Org. Chem.
2004, 1, 268.
Having in hand an efficient protocol for C-2 selective addition
of 2-(2-chlorophenyl)-4-isobutyloxazol-5(4H)-one 2a to (E)-
dimethyl but-2-enoylphosphonate 1a, we explored the scope of
the reaction of various oxazolones and alcohols/amines in the
double nucleophilic reaction with aliphatic acyl phosphonates,
and the results are presented in Table 2. Various aliphatic side
chains at the C-4 position of the oxazolone were evaluated
(2a-c) all forming the desired C-2 alkylated products 4a-c as
single diastereomers. Increased the steric bulk had minor effects
on the enantioselectivity (compare Table 2, entries 1, 2, 4) and
by using the quasienantiomer of the catalyst (3a), the opposite
(10) For reviews on synthesis of R,R-disubstituted R-amino acids, see. (a)
Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron: Asymmetry 1998,
9, 3517. (b) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 2000, 11, 3517. (c) Ohfune, Y.; Shinada, T. Eur. J. Org.
Chem. 2005, 5127. (d) Vogt, H.; Bra¨se, S. Org. Biomol. Chem. 2007,
5, 406.
9
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A R T I C L E S
Jiang et al.
Table 2. Scope of the C-2 Selective Addition of Oxazolones to
The obtained optically active products 4 might undergo a
number of transformations leading to various useful functional
groups,8h thus highlighting the synthetic relevance of the
stereoselective addition reaction. We will only present two
transformations (Scheme 4).
Acyl Phosphonatesa g
,
Treatment of the C-2 addition product 4i with NaBH4 led to
the formation of a single product identified as compound 5
(Scheme 4, left). Apparently, despite the presence of several
reduction-prone sites, the activated lactone motif is selectively
targeted, furnishing the surprisingly stable γ-lactol product 5
in 75% yield after purification on silica gel. Literature reports
show that addition of organometallic reagents such as Grignard
reagents also occurs selectively to the lactone motif of the
oxazolone in the presence of esters and imines.13
Ring-opening of the oxazolone moiety also proved to be
possible, as exemplified for the formation of Stetter product 6
(from 4k).14 Initial investigations revealed that acidic or Lewis
acidic conditions promoted the desired product in either low
yield or as a racemate. Treating the C-2 addition adduct with
weak base under gentle heating proved to be the most suitable
condition in respect to selectivity of reaction and preservation
of optical integrity.15 As presented in Chart 1, even under these
fairly mild conditions, rapid racemization of product 6 is
observed, leaving nearly racemic products after 14 h of reaction.
Quenching of the reaction mixture after 2 h afforded the desired
product 6 in 40% yield (45% conversion) and 84% ee, while
unreacted starting material is easily recovered (48%) with the
same optical purity as applied (Scheme 4, right). It should be
noted that this class of products (as 6) has usually been
accessible by chiral carbene catalysis or the use of a stoichio-
metric amount of optically active reagents.15
entry
R1
R2/R3
nucleophile
yield (%)b
ee (%)c
1
2
3
Me (1a) iBu/o-Cl-Ph (2a) MeOH
Me (1a) iPr/o-Cl-Ph (2b) MeOH
Me (1a) iPr/o-Cl-Ph (2b) MeOH
Me (1a) tBu/o-Cl-Ph (2c) MeOH
Me (1a) iPr/o-Cl-Ph (2b) EtOH
Me (1a) iPr/o-Cl-Ph (2b) BnOH
Me (1a) iPr/o-Cl-Ph (2b) BnNH2
67 (4a)
63 (4b)
90
93
57 (ent-4b)e -90
4
74 (4c)
55 (4d)
50 (4e)
79 (4f)
91
92
88
90
86
90
92
82
95
94
99f
5d
6
7
8
9
10
11
Me (1a) iPr/o-Cl-Ph (2b) Morpholine 30 (4g)
Me (1a) iBu/o-F-Ph (2d) MeOH
Me (1a) iPr/o-Br-Ph (2e) MeOH
Me (1a) iPr/o-Me-Ph (2f) MeOH
74 (4h)
73 (4i)
56 (4j)
71 (4k)
62 (4l)
12d Pr (1b)
iPr/o-Br-Ph (2e) MeOH
13d Hex (1c) iPr/o-Br-Ph (2e) MeOH
14
Me (1a) tBu/o-Cl-Ph (2c) p-Br-BnNH2 50 (4m)
a Unless otherwise stated, 0.1 of mmol 1a, 0.3 of mmol 2a and 0.01
mmol of 3b were reacted at -20 °C for 24-48 h. [1] ) 0.2 M.
b Isolated yield. c Determined by chiral stationary phase HPLC. d 1a (0.3
mmol) and 2a (0.1 mmol) were employed. [2] ) 0.2 M. e Catalyst 3a
was used. f Performed on 0.2 mmol scale. Yield and ee determined after
single recrystallization (CHCl3/n-hexane). g Other substitution patterns
are also allowed on the phenyl ring; however, chiral separation for
determination of ee was not possible for these compounds.
Chart 1. Racemization in Oxazolone Opening of 4k
Figure 2. X-ray structure of compound 4m.
enantiomer of the product was formed (entry 3). Alternatively,
when the reaction intermediate was quenched with EtOH or
BnOH, the corresponding ethyl and benzyl ester adducts 4d,e were
obtained, while the use of BnNH2 and morpholine as the nucleo-
philic partners rendered the requested amide products 4f,g (entries
5-8). The aryl group attached to C-2 position can also be altered,
as different electron-withdrawing (entries 9, 10) and donating
substituents (entry 11) can be applied, giving the products 4h-j
in 56-74% yield and 82-92% ee. Finally, other aliphatic acyl
phosphonates 1b,c were reacted with oxazolone 2e under the same
reaction conditions, furnishing the desired optically active esters
4k,l in 62-71% yield and 94-95% ee (entries 12, 13). The
absolute configuration of the product 4m is unequivocally estab-
lished to be (R,R) by X-ray analysis (Figure 2)12 and the remaining
configurations are assumed by analogy.
As proposed in Figure 1, the regioselectivity of the addition
of oxazolones to acyl phosphonates is believed to be controlled
by both catalyst and substituents on the nucleophile. Conse-
quently, careful selection of catalyst may lead to regioreversal
addition from C-2 to C-4 carbon center. On the basis of the
considerations in Figure 1, we initiated our investigation by
using thiourea 3c derived from enantiopure (1S,2R)-1-amino-
indan-2-ol as H-bonding catalyst.16 To our delight, exchange
of the basic site of the cinchona-derived catalyst 3a,b with an
Scheme 4. Transformations of the C-2 Addition Adducts 4i,k
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Acyl Phosphonates
A R T I C L E S
additional hydroxy-directing group switches the regioselectivity
completely from C-2 to C-4 addition (Table 3). The reaction
between (E)-dimethyl but-2-enoylphosphonate 1a and 2-(2-
chlorophenyl)-4-isobutyloxazol-5(4H)-one 2a afforded upon
quenching with DBU and MeOH the open quaternary amino
acid derivative 7 as the single product in 53% yield, albeit with
a low enantiomeric excess of 13% ee (entry 1). The change of
the regioselectivity suggests that the nature of the chiral
functional group of the catalyst is essential for the outcome of
the reaction. Several other chiral thioureas were evaluated as
catalysts of the regioreversal C-4 addition reaction; however,
only low to moderate regio- and enantioselectivities were
observed. The best results were obtained using catalyst 3a in
combination with organic acids as additives, thereby protonating
the basic quinuclidine and quinoline motifs.17 By only employ-
ing 10 mol % of TFA as cocatalyst, a 2:1 mixture of product
4a and 7 is formed (entry 2). Increasing the amount to 50 mol
% gave exclusively and directly the desired C-4 addition amino
acid product 7, albeit in racemic form (entry 3). A catalyst/acid
ratio of 1:2 proved to be the optimum condition, forming 7 in
excellent regioselectivity and moderate enantioselectivity (entry
4). Substituting TFA with other acids such as L-proline had no
influence on the stereochemical outcome of the reaction (entry
7), while temperature alterations lowered the enantioselectivity
considerably (entries 5, 6). The results demonstrate that the
nature of the chiral functional group in the catalyst is essential
for the regioselectivity of the addition reaction. Furthermore,
under standard conditions when the aromatic C-2 substituent
of the oxazolone is replaced with an alkylic chain, such as tBu,
a mixture of C-2 and C-4 addition products is formed with
moderate enantio- and diastereoselectivity, stating the impor-
tance of substitution pattern in control of regioselectivity.
continuance of our exploration of acyl phosphonates as a
powerful ester/amide surrogate in asymmetric H-bonding ca-
talysis, we continued the evaluation of other carbon-based
nucleophiles suitable for the catalytic system. The Friedel-Crafts
alkylation also represents one of the cornerstones in organic
chemistry. The robustness of the reaction and the diversity, with
which elemental starting materials can be converted, has driven
unrelenting developments in this field of research for more than
a century. During the past decade, a number of asymmetric
catalytic variants of the Friedel-Crafts alkylation have been
reported18 and enantioselective addition of aromatic compounds
to electron-poor alkenes has been realized for electrophiles such
as nitroalkenes, enals, enones, and unsaturated R-keto esters.
In 2003, Evans et al. reported a formal Friedel-Crafts alkylation
of esters and amides using acyl phosphonates and a chiral
scandium complex as electrophile and catalyst, respectively.3c
(11) For a first synthesis, see. (a) Vakulya, B.; Varga, S.; Csampai, A.;
Soo´s, T. Org. Lett. 2005, 7, 1967. For selected examples, see (b)
McCooey, S. H.; Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367.
(c) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481.
(d) Vakulya, B.; Varga, S.; Soo´s, T. J. Org. Chem. 2008, 73, 3475.
(e) Elsner, P.; Jiang, H.; Nielsen, J. B.; Pasi, F.; Jørgensen, K. A.
Chem. Commun. 2008, 5827. (f) Biddle, M. M.; Lin, M.; Scheidt,
K. A. J. Am. Chem. Soc. 2007, 129, 3830. (g) Wang, J.; Li, H.; Zu,
L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem. Soc. 2006,
128, 12652. (h) Wang, Y.-Q.; Song, J.; Hong, R.; Li, H.; Deng, L.
J. Am. Chem. Soc. 2006, 128, 8156. (i) Giola, C.; Hauville, A.;
Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem., Int. Ed. 2008, 47, 9236.
For other cinchona-alkaloid-based thiourea catalysts, see (j) Marcelli,
T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem., Int. Ed. 2006, 45, 929. (k) Dickmeiss, G.; De Sio, V.; Udmark,
J.; Poulsen, T. B.; Marcos, V.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2009, 48, 6650.
(12) CCDC 752315 contains the supplementary crystallographic data.
These data can be obtained free of charge at www.ccdc.cam.ac.uk/
conts/ retrieving.html [or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336-
033.
Table 3. C-4 Addition of
2-(2-Chlorophenyl)-4-isobutyloxazol-5(4H)-one 2a to Acyl
Phosphonate 1a
(13) Leyendecker, J.; Niewoehner, U.; Steglich, W. Tetrahedron Lett. 1983,
24, 2375.
(14) For recent review on the Stetter reaction, see Christmann, M. Angew.
Chem., Int. Ed. 2005, 44, 2632, and references herein.
(15) (a) Schulz, G.; Steglich, W. Chem. Ber. 1980, 113, 787. For other
literature-described methods, see. (b) Niewo¨hner, U.; Steglich, W.
Angew. Chem., Int. Ed. 1981, 20, 395.
(16) For previous studies using the aminoindanol-derived catalyst, see. (a)
Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem.,
Int. Ed. 2005, 44, 6576. (b) Lattanzi, A. Synlett 2007, 2106. (c) Herrera,
R. P.; Monge, D.; Mart´ın-Zamora, E.; Fernande´z, R.; Lassaletta, J. M.
Org. Lett. 2007, 9, 3303. See also ref 2c.
(17) For study on the basicity and nucleophilicity of the two nitrogen centers
in cinchona alkaloids, see. (a) Maida, M.; Horn, M.; Zipse, H.; Mayr,
H. J. Org. Chem. 2009, 74, 7157. (b) Baidya, M.; Kobayashi, S.;
Brotzel, F.; Schmidhammer, U.; Riedle, E.; Mayr, H. Angew. Chem.,
Int. Ed. 2007, 46, 6176.
entry
catalyst
additive (mol %)
T (°C)
4a:7b
ee (%)c
(18) For a recent review on asymmetric Friedel-Crafts reaction, see. (a)
Poulsen, T. B.; Jørgensen, K. A. Chem. ReV. 2008, 108, 2903, and
references therein. (b) Jørgensen, K. A. Synthesis 2003, 1117. (c)
Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int., Ed.
2004, 43, 550. (d) Bandini, M.; Melloni, A.; Tommasi, S.; Umani-
Ronchi, A. Synlett 2005, 1199. (e) You, S.-L.; Cai, C.; Zeng, M. Chem.
Soc. ReV. 2009, 38, 2190. For recent examples of organocatalytic
Friedel-Crafts alkylations, see (f) Itoh, J.; Fuchibe, K.; Akiyama, T.
Angew. Chem., Int. Ed. 2008, 47, 4716. (g) Cai, C.; Zhao, Z.-A.; You,
S.-L. Angew. Chem., Int. Ed. 2009, 48, 7428. (h) Wang, Y.-Q.; Song,
J.; Hong, R.; Li, H.-M.; Li, D. J. Am. Chem. Soc. 2006, 128, 8156. (i)
Terada, M.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129, 292. (j) Paras,
N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2001, 123, 4370. (k)
Bartoli, G.; Bosco, M.; Carlone, A.; Pesciaioli, F.; Sambri, L.;
Melchiorre, P. Org. Lett. 2007, 9, 1403. For recent examples using
metal-catalysis, see (l) Trost, B. M.; Mu¨ller, C. J. Am. Chem. Soc.
2008, 130, 2438. (m) Palomo, C.; Oiarbide, M.; Kardak, B. G.; Garc´ıa,
J. M.; Linden, A. J. Am. Chem. Soc. 2005, 127, 4154. (n) Singh, P. K.;
Singh, V. K. Org. Lett. 2008, 10, 4121. (o) Liu, H.; Xu, J.; Du, D.-M.
Org. Lett. 2007, 9, 4725. (p) Blay, G.; Fernande´z, I.; Pedro, J. R.;
Vila, C. Org. Lett. 2007, 9, 2601.
1
2
3
4
5
6
7
3c
3a
3a
3a
3a
3a
3b
-
rt
4
4
4
-20
40
4
5:95 (53%)d
2:1
5:95
5:95 (60%)
5:95
5:95
13
nd
0
55
30
0
TFA (10)
TFA (50)
TFA (20)
TFA (20)
TFA (20)
L-proline (20)
5:95
-50
a Unless otherwise stated, 0.1 mmol of 1a, 0.3 mmol of 2a, 0.01
mmol of 3 and the appropriate additive were reacted at the given
temperature until completion of the reaction as monitored by TLC
(usually 4-48 h). b Determined by NMR of the crude reaction mixture.
No distereoselectivity of product 7 was achieved. In parentheses is the
given yield of isolated product. c Determined by chiral stationary phase
HPLC. d A single diastereomer of 7 was isolated.
Friedel-Crafts Alkylation. Encouraged by the results ob-
tained in the oxazolone addition to acyl phosphonates and in
9
J. AM. CHEM. SOC. VOL. 132, NO. 8, 2010 2779

A R T I C L E S
Jiang et al.
Table 4. Screening of the Friedel-Crafts Alkylation of (E)-Dimethyl But-2-enoylphosphonate 1a with Indole 8a
entry
catalyst
solvent
T (°C)
[8a] (M)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
3c
3d
3e
3f
CH2Cl2
rt
rt
rt
rt
rt
-30
rt
rt
rt
rt
-20
-30
-40
-20
-20
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
0.05
87
40
37
34
82
93
85
17
74
10
81
73
61
65
60
74
0
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
MeCN
0
3g
3h
3c
3c
3c
3c
3c
3c
3c
3c
3c
60
20
64
49
74
39
79
79
79
81
86
9
ClCH2CH2Cl
THF
10
11
12
13
14
15d
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
a Unless otherwise stated, all reactions were performed with 0.1 mmol of 1a and 8a and 0.01 mmol of catalyst 3 at the given temperature. Reactions
performed at rt were quenched after 4 h. For other temperatures, quenching occurred after 40 h. b Isolated yield. c Determined by chiral stationary phase
HPLC. d Performed with 0.2 mmol of 1a and 0.1 mmol of 8a.
As will be apparent in the following, comparably good results
can be achieved using metal-free conditions and by application
of chiral thiourea catalysts.
obtained in apolar solvents such as toluene; however, a small
decrease in enantioselectivity was observed compared with
CH2Cl2 (entry 7). Other polar aprotic solvents such as MeCN
or THF had a destructive effect on the rate of the reaction
forming 9a in <20% yield and <50% ee after 4 h of reaction
(entries 8, 10). It was only in other chlorinated solvents such
as DCE that results similar to those obtained with CH2Cl2 were
reached (entry 9). Decreasing the temperature of the reaction
to -20 °C had a positive effect on the enantioselectivity (entry
11), while lowering the temperature further gave no improve-
ments (entries 12, 13). Lastly, dilution of the reaction mixture
and the use of 2 equiv of 1a provided the final enhancement in
terms of selectivity, affording 9a in 60% yield and 86% ee (entry
15).
Complementary to the work of Evans et al. focusing on the
use of N-alkylated indoles as nucleophiles, we turned our
attention toward the corresponding NH-free counterparts. The
initial screening results are as outlined in Table 4. Various amino
indanol derived catalysts 3c-h were evaluated for the reaction
between (E)-dimethyl but-2-enoylphosphonate 1a and indole 8a
in CH2Cl2. It appears that a free hydroxy group and the syn-
relation between the hydroxy and thiourea moiety proved to be
decisive for the reactivity and the enantioselectivity of the
reaction. Application of thiourea 3c as catalyst afforded the
ꢀ-arylated ester product 9a in 87% yield and 74% ee (Table 4,
entry 1). Instead, changing the configuration of the two
functional groups of the catalyst to trans (3e) diminished both
the yield and selectivity (entry 3). Similar poor results were
observed using O-silylated catalysts 3d,f (entries 2, 4). It is
previously reported that the squarate motif provides better
coordination than thioureas because of increased H-bond
distance and H-donor capacity.19 By employing a squaramide
3g as chiral inducer, product 9a was formed with slightly lower
enantioselectivity (entry 5). The protonated catalyst 3h20 also
afforded the product in excellent yield; however, the enantio-
selectivity (20% ee) was disappointing (entry 6). Having
confirmed 3c as the optimum catalyst for the reaction, a simple
solvent screening was carried out. Excellent reactivity was
To demonstrate the scope of the organocatalytic Friedel-Crafts
alkylation, a plethora of indoles 8 and alcohol/amine nucleo-
philes were evaluated for the reaction with the acyl phosphonates
1a,b (Table 5). Using EtOH instead of MeOH for the in situ
acyl substitution led to an increase in the enantioselectivity,
forming the ꢀ-functionalized ethyl ester product 9b in 68% yield
and 90% ee (entries 1, 2). To validate that a broad range of
ester and amide products can be accessed, a representative
selection of alcohols and amines were employed, forming the
arylated adducts 9a-e in 80-90% ee (entries 1-5).
Interestingly, the optical purity of the obtained ester or amide
products seems to be dependent on the applied nucleophilic
species. It has been observed that a partial racemization can
take place in the optically ꢀ-arylated acyl phosphonate during
the second nucleophilic attack. The degree of racemization is
presumably influenced by the nucleophilicity and basicity of
(19) Malerich, J.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008,
130, 14416.
(20) Ganesh, M.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 16464.
9
2780 J. AM. CHEM. SOC. VOL. 132, NO. 8, 2010

Acyl Phosphonates
A R T I C L E S
Table 5. Scope of the Organocatalytic Friedel-Crafts Alkylation Reaction
entry
R1 (1)
R2/R3/R4/R5 (8)
nucleophile
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Pr (1b)
H/H/H/H (8a)
H/H/H/H (8a)
H/H/H/H (8a)
H/H/H/H (8a)
H/H/H/H (8a)
OMe/H/H/H (8b)
H/OMe/H/H (8c)
H/H/OMe/H (8d)
H/OMe/H/Me (8e)
H/Cl/H/H (8f)
H/I/H/H (8g)
MeOH
EtOH
BnOH
BnNH2
morpholine
EtOH
EtOH
EtOH
EtOH
EtOH
60 (9a)
68 (9b)
57 (9c)
63 (9d)
63 (9e)
93 (9f)
74 (9g)
84 (9h)
87 (9i)
86 (9j)
70 (9k)
92 (9l)
86
90
83
80
87
90
82
83
85
90
85
72
9
10
11
12d
EtOH
EtOH
H/H/H/H (8a)
a Unless otherwise stated, all reactions were performed with 0.2 mmol of 1, 0.1 mmol of 8 and 0.01 mmol of 3c in 2 mL of CH2Cl2 at -20 °C. The
reactions were quenched the appropriate alcohol/amine upon completion of reaction, usually after 40-60 h. b Isolated yield. c Determined by chiral
stationary phase HPLC. d Performed at 0 °C.
the chosen nucleophile, and reaction time. We have noted that
prolonged reaction time for the second nucleophilic attack can
lead to a further racemization as, for example, observed for the
ethyl ester adduct 9b (90% ee) which was recovered with only
68% ee when stirred with DBU and BnOH for 24 h.
Additionally, we demonstrate that the described Friedel-Crafts
alkylation is unbiased toward substitution on the indole nucleo-
philes. Having an electron-donating substituent at various
positions on the indole ring was tolerated, furnishing the desired
addition products 9f-i in 74-93% yield and 82-90% ee (Table
5, entries 6-9). Moreover, electron-poor indoles such as 8f and
8g could also be included as reaction partners. Under the
optimized conditions, the ꢀ-arylated ethyl esters 9j,k were
afforded in 90% and 85% ee, respectively. Variation of the side
chain of the acyl phosphonate is also possible as shown for
substrate 1b, leading to isolation of 9l in 92% yield and 72%
ee.
providing only low conversion after prolonged reaction times
when reacting methyl 2-oxocyclopentanecarboxylate 10a with
electrophile 1a. Inspired by recent work of Rawal et al.,19 we
turned our attention toward the use of chiral cinchona alkaloid
derived squaramides as the H-bonding motif. Gratifyingly, the
squaramide catalyst 3i that originated from cinchonine catalyzed
the reaction to full conversion within 40 h, forming the desired
Michael adduct ent-11a in 73% yield, 10:1 dr, and 91% ee as
presented in Scheme 5. Synthesizing catalyst 3j using quinine
as the chiral scaffold allowed access to the opposite enantiomer
of the product (11a) in similar yield and diastereoselectivity,
and slightly higher enantioselectivity (95% ee). Quenching the
reaction with EtOH or BnNH2 as nucleophiles afforded the ethyl
ester 11b or benzyl amide 11c in 94% and 92% ee, respectively.
Increased steric bulk of the ester group had a diminishing effect
with respect to yield (65%) and enantioselectivity (88% ee) of
the product 11d, while the diastereoselectivity remained unaf-
1,3-Dicarbonyl Addition. Nowadays, developments in C-C
bond-forming reactions with an aim for rapid and stereoselective
generation of all carbon quaternary stereocenters has evolved
as a major area of interest.21 In this respect, addition of activated
carbon nucleophiles such as 1,3-dicarbonyl compounds to
electron-poor alkenes represents an obvious and straightforward
reaction strategy. However, while the asymmetric catalytic
conjugate addition of simple malonates and nonsubstituted
ꢀ-ketoesters is well described in the literature, reactions between
R-substituted 1,3-dicarbonyls and ꢀ-substituted Michael accep-
tors leading to the formation of two stereogenic centers (of
which one is quaternary all carbon) are more difficult. The
primary challenge lies with the efficient control of both the
enantio- and diastereoselectivity of the reaction. The use of
enals, enones, and nitroalkenes as electrophiles in such reactions
has been realized using metal or organocatalysts with varying
success.22 To the best of our knowledge, the addition of prochiral
R-substituted 1,3-dicarbonyl compounds to esters or surrogates
has not been performed with good enantioselectivity. We
envisioned that by reacting acyl phosphonates with cyclic 1,3-
dicarbonyl compounds in combination with H-bonding catalysis,
ester or amide products carrying an all-carbon stereocenter can
be formed. Initial catalyst screening indicated that thiourea
catalysts such as 3a,b were inefficient as a rate enhancer,
(21) For recent reviews, see. (a) Trost, B. M.; Jiang, C. Synthesis 2006,
369. (b) Christoffers, J.; Baro, A. AdV. Synth. Catal. 2005, 347, 1473.
(c) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5363. (d) Ramon, D. J.; Yus, M. Curr. Org. Chem. 2004, 8, 149.
(e) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem.
2007, 5969. For selected examples, see (f) Ma, S.; Han, X.; Krishnan,
S.; Virgil, S. C.; Stoltz, B. M. Angew. Chem., Int. Ed. 2009, 48, 8037.
(g) Hashimoto, T.; Sakata, K.; Maruoka, K. Angew. Chem., Int. Ed.
2009, 48, 5014. (h) May, T. L.; Brown, K.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2008, 47, 7358. (i) Martin, D.; Kehrli, S.; d’Augustin,
M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006,
128, 8416. (j) Zhang, E.; Fan, C.-A.; Tu, Y.-Q.; Zhang, F.-M.; Song,
Y.-B. J. Am. Chem. Soc. 2009, 131, 14626. (k) Smejkal, T.; Han, H.;
Breit, B.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 10366. (l)
Zhang, A.; Rajanbadu, T. V. J. Am. Chem. Soc. 2006, 128, 5620. (m)
Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc. 2005,
127, 4584. (n) Hishimoto, T.; Naganawa, Y.; Maruoka, K. J. Am.
Chem. Soc. 2009, 131, 6614.
(22) For a recent short review, see (a) Christoffers, J.; Baro, A. An-
gew.Chem. Int. Ed. 2003, 42, 1688. For selected examples, see (b)
Hamashima, Y.; Hotta, D.; Umebayashi, N.; Tsuchiya, Y.; Suzuki,
T.; Sodeoka, M. AdV. Synth. Catal. 2005, 347, 1576. (c) Sasai, H.;
Emori, E.; Arai, T.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 5561.
(d) Palomo, C.; Oiarbide, G. J. M.; Banuelos, P.; Odriozola, J. M.;
Razkin, J.; Linden, A. Org. Lett. 2008, 10, 2637. (e) Capuzzi, M.;
Perdicchia, D.; Jørgensen, K. A. Chem.sEur. J. 2008, 14, 128. (f)
Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583.
(g) Ooi, T.; Miki, T.; Taniguchi, M.; Shiraishi, M.; Takeuchi, M.;
Maruoka, K. Angew. Chem., Int. Ed. 2003, 42, 3796. See also ref 20.
9
J. AM. CHEM. SOC. VOL. 132, NO. 8, 2010 2781

A R T I C L E S
Jiang et al.
fected. Substrate scope could be further broadened to include a
cyclic lactone and 1,3-diketone, giving rise to the formation of
compounds 11e,f in 60% yield, 4:1 dr, 92% ee, and 57% yield,
>15:1 dr, 87% ee, respectively.
placing the alkene side chain out to the steric less-demanding
area away from the C-9 center of the catalyst, while the 1,3-
dicarbonyl compound is deprotonated and directed for the
nucleophilic attack by the tertiary nitrogen atom of the catalyst
(Scheme 7). The R2-group of the nucleophile is oriented away
from the reaction site and the subsequent conjugate addition
approaches to the Si-face of the CdC bond, accounting for both
the enantio- and diastereoselectivity of the reaction.
Scheme 5. Addition of Cyclic 1,3-Dicarbonyl Compounds to
(E)-Dimethyl But-2-enoylphosphonate 1a
Scheme 7. Mechanistic Considerations for the Approach of
1,3-Dicarbonyl Compounds to the Acyl Phosphonate Coordinated
to the Thiourea Catalyst 3j
An interesting aspect appeared when comparing the stereo-
chemical outcome of the oxazolone and 1,3-dicarbonyl addition
products 4 and 11. It appears that by using another quinine-
derived catalyst 3b, the C-2 addition of the oxazolone to acyl
phosphonate takes place to the Re-face of the CdC-bond, in
contrast to the Si-face approach of the 1,3-dicarbonyl addition.23,24
The squaramide catalyst 3j used for the 1,3-dicarbonyl addition
(Si-face selective) can also be applied for the oxazolone C-2
addition resulting in selective Re-face attack (70% ee), thereby
ruling out the influence of the H-bonding motif of the catalyst
(squarate vs thiourea). A plausible explanation may be a form
of “induced fit” property of the cinchona catalyst in the transition
state, where the oxazolone and 1,3-dicarbonyl compounds trigger
different conformations of the substrate-catalyst complex. As
presented in Scheme 8, top left, the oxazolone might react as
its enolate, having character of an electron-rich aromatic
compound, which might form π-π interactions with the
electron-poor aryl group adjacent to the thiourea motif. It is
tentatively proposed that this interaction brings the quinuclidine
group (also coordinated to the oxazole enolate) closer to the
aryl thiourea moiety, forming a “closed” conformation of the
catalyst which projects the olefin side chain of the acyl
phosphonate away from the 3,5-bistrifluoromethyl aryl group
because of steric hindrance, resulting in Re-face attack of the
nucleophile and a stereochemical outcome of the reaction in
accordance with the experimental results.
Mechanistic Aspects. The stereochemical course of the
different reactions show some interesting outcomes. In the
Friedel-Crafts alkylation, the absolute configuration of product
9a is determined to be 3R, by chemical correlation to previous
reports (see Supporting Information). Remaining configurations
of the Friedel-Crafts products 9 are assumed by analogy. In
contrast to the work by Evans et al., using N-alkylated indoles
as nucleophiles, the present indole nucleophiles require the free
indole-NH functionality, as the N-methylated analogue gave a
much slower reaction and a racemic product. Thus, catalyst 3c
is believed to direct the approach of the indole to the acyl
phosphonate with weak hydrogen bonding to the indolic
proton,16 while the electrophile is activated and positioned for
the nucleophilic attack from the Re-face by the thiourea motif
as outlined in Scheme 6.
Scheme 6. Mechanistic Considerations for the Approach of Indole
to the Acyl Phosphonate Coordinated to the Thiourea Catalyst 3c
The alternative is an “open” form catalyst conformation as
postulated in the mechanism of the 1,3-dicarbonyl addition; in
this case the olefin of the acyl phosphonate is placed in the
opposite direction compared to the “closed” conformation, thus
favoring a Si-face attack, Scheme 8, top right. However, in this
(23) Absolute configuration determined by chemical correlation to
ref 22b.
(24) Similar observations could be made by inspection and comparison of
previous literature reports, where the cinchona-alkaloid-based H-
bonding catalysts were employed. However, such an “inversion” of
addition pattern has not been discussed previously (compare refs
8b,11c, 19).
The stereoselectivity of the 1,3-dicarbonyl addition to acyl
phosphonates is believed to origin from bifunctional coordina-
tion of the nucleophilic and electrophilic reaction partners to
the quinine-derived catalyst 3j. It is proposed that the acyl
phosphonate is hydrogen bonded to the squaramide motif,
9
2782 J. AM. CHEM. SOC. VOL. 132, NO. 8, 2010

Acyl Phosphonates
A R T I C L E S
Scheme 8. Different Mechanistic Considerations for the Approach of Oxazole Enolate to the Acyl Phosphonate Coordinated to the Catalysts
3b,j
case, the “open” catalyst conformation neglects the positive π-π
interactions and is therefore disfavored (in contrast to the 1,3-
dicarbonyl addition, where no π-π interactions are present).
Another possible indication of two conformations of the
catalyst-substrate complex is observed when using a catalyst
with an additional methylene between the H-bonding motif and
the electron-deficient aryl group (3j). The increased flexibility
and extended distances lead to a more flexible “closed”
conformation of the substrate-catalyst complex, and this loss
of rigidity results in inferior control and slightly reduced enantio-
and diastereoselectivity (70% ee and 5:1 dr). Another possibility
is a change in operational pathway of the catalyst, such as self-
association of the cinchona alkaloid catalyst, as noncovalent
dimers have been observed.25
indoles, and cyclic 1,3-dicarbonyl compounds. Moreover, it is
shown that the acyl phosphonates may serve as masked ester
or amide equivalents which upon quenching generated the parent
structures in situ. The presented approach allows for an efficient
route to formal ꢀ-functionalizations of simple esters and amides,
affording a broad spectrum of optically active conjugate adducts
in good yields and excellent enantioselectivities. Hence, the use
of acyl phosphonates in combination with hydrogen-bonding
catalysis may serve as a general template for formal ester/amide
functionalization. The mechanism for activation of both the acyl
phosphonate and indole, oxazolone, and 1,3-dicarbonyl com-
pounds, as well as the stereoselective approach of the latter to
the olefin in the conjugated addition reaction, by the chiral
catalyst is also presented.
Conclusion
Acknowledgment. This work was made possible by grants from
Danish National Research Foundation, Carlsberg Foundation, and
OChemSchool. D.M. thanks the “Ministerio de Ciencia e Innova-
cio´n” of Spain for a postdoctoral fellowship.
We have demonstrated that unsaturated acyl phosphonates
are excellent hydrogen-bond acceptors in enantioselective
organocatalysis. A variety of highly stereoselective conjugate
additions to R,ꢀ-unsaturated acyl phosphonates were performed,
using different carbon-based nucleophiles such as oxazolones,
Supporting Information Available: Complete experimental
procedures and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
(25) (a) Hamza, A.; Schubert, G.; Soos, T.; Papai, I. J. Am. Chem. Soc.
2006, 128, 13151. (b) Tarkanyi, G.; Kiraly, P.; Varga, S.; Vakulya,
B.; Soos, T. Chem.sEur. J. 2008, 14, 6078.
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