A general organocatalyst for direct α-functionalization of aldehydes: Stereoselective C-C, C-N, C-F, C-Br, and C-S bond-forming reactions. Scope and mechanistic insights

Article abstract of DOI:10.1021/ja056120u

The development of a general organocatalyst for the α- functionalization of aldehydes, via an enamine intermediate, is presented. Based on optically active α,α-diarylprolinol silyl ethers, the scope and applications of this catalyst for the stereogenic fo

Full text of DOI:10.1021/ja056120u

Published on Web 12/03/2005
A General Organocatalyst for Direct r-Functionalization of
Aldehydes: Stereoselective C-C, C-N, C-F, C-Br, and C-S
Bond-Forming Reactions. Scope and Mechanistic Insights
Johan Franze´n, Mauro Marigo, Doris Fielenbach, Tobias C. Wabnitz,
Anne Kjærsgaard, and Karl Anker Jørgensen*
Contribution from the The Danish National Research Foundation: Center for Catalysis,
Department of Chemistry, Aarhus UniVersity, DK-8000 Aarhus C, Denmark
Received September 12, 2005; E-mail: kaj@chem.au.dk
Abstract: The development of a general organocatalyst for the R-functionalization of aldehydes, via an
enamine intermediate, is presented. Based on optically active R,R-diarylprolinol silyl ethers, the scope and
applications of this catalyst for the stereogenic formation of C-C, C-N, C-F, C-Br, and C-S bonds are
outlined. The reactions all proceed in good to high yields and with excellent enantioselectivities. Furthermore,
we will present mechanistic insight into the reaction course applying nonlinear effect studies, kinetic
resolution, and computational investigations leading to an understanding of the properties of the
R,R-diarylprolinol silyl ether catalysts.
Introduction
among the others for their application in a broad range of
transformations.
We are in “the golden age of organocatalysis”, and organo-
catalytic reactions have in the past few years emerged as a
powerful tool for the preparation of optically active compounds.1
The use of chiral secondary amines for the R-functionalization
of aldehydes represents an important breakthrough in modern
asymmetric synthesis and a large variety of functionalizations,
such as C-C,2 C-N,3 C-X (X ) halogen),4 C-S,5 C-O6
bond-forming reactions among others, have been developed.
As a result of the thoroughly investigated R-functionalization
of aldehydes, numerous different secondary amine-based cata-
lysts have been developed. In many cases this leads to a very
tedious screening of a large number of catalysts when develop-
ing new reactions because only a few organocatalysts stand out
Proline is certainly part of this noble club, and in the recent
past, it has been defined as a “universal catalyst” because of its
high utility especially in enantioselective aldol,7 Mannich,8
amination,3 and R-aminoxylation reactions.6a-e The catalysts
developed in the laboratories of MacMillan et al. also show an
interesting generality and were found effective for chlorination,4e
(5) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2005, 44, 794.
(6) (a) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2003, 125, 10808. (b) Zhong, G. Angew. Chem., Int. Ed. 2003,
42, 4247. (c) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron
Lett. 2003, 44, 8293. (d) Zhong, G.; Yu, Y. Org. Lett. 2004, 6, 1637. (e)
Co´rdova, A.; Sunde´n, H.; Bøgevig, A.; Johansson, M.; Himo F. Chem.s
Eur. J. 2004, 10, 3673. (f) Co´rdova, A.; Sunde´n, H.; Engqvist, M.; Ibrahem,
I.; Casas, J. J. Am. Chem. Soc. 2004, 126, 8914.
(7) (a) List, B.; Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122,
2395. (b) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III. J. Am. Chem.
Soc. 2001, 123, 5260. (c) Co´rdova, A.; Notz, W.; Barbas, C. F., III. J.
Org. Chem. 2002, 67, 301. (d) Northrup, A. B.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2002, 124, 6798. (e) Bøgevig, A.; Kumaragurubaran, N.;
Jørgensen, K. A. Chem. Commun. 2002, 620. (f) Tang, Z.; Jiang, F.; Yu,
L.-T.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. J. Am.
Chem. Soc. 2003, 125, 5262. (g) Mase, N.; Tanaka, F.; Barbas, C. F., III.
Angew. Chem., Int. Ed. 2004, 43, 2420. (h) Torii, H.; Nakadai, M.; Ishihara,
K.; Saito, S.; Yamamoto, H. Angew. Chem., Int. Ed. 2004, 43, 1983. (i)
Artikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831. (j)
Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 3541.
(k) Kofoed, J.; Nielsen, J.; Reymond, J.-L. Bioorg. Med. Chem. Lett. 2003,
13, 2445. (l) Chandrasekhar, S.; Narsihmulu, Ch.; Reddy, N. R.; Sultana,
S. S. Chem. Commun. 2004, 2450. (m) Allemann, C.; Gordillo, R.;
Clemente, F. R.; Cheong, P. H.; Houk, K. N. Acc. Chem. Res. 2004, 37,
558.
(8) (a) Notz, W.; Sakthivel, K.; Bui, T.; Barbas, C. F., III. Tetrahedron Lett.
2001, 42, 199. (b) Co´rdova, A.; Notz, W.; Zhong, G.; Betancort, J. M.;
Barbas, C. F., III. J. Am. Chem. Soc. 2002, 124, 1842. (c) Co´rdova, A.;
Watanabe, S.-I.; Tanaka, F.; Notz, W.; Barbas, C. F., III. J. Am. Chem.
Soc. 2002, 124, 1866. (d) Chowdari, N. S.; Ramachary, D. B.; Barbas, C.
F., III. Synlett. 2003, 1906. (e) Notz, W.; Tanaka, F.; Watanabe, S.-I.;
Chowdari, N. S.; Thayumanavan, R.; Barbas, C. F., III. J. Org. Chem. 2003,
68, 9624. (f) List, B.; Pojarliev, P.; Biller, W. T.; Martin, H. J. J. Am.
Chem. Soc. 2002, 124, 827. (g) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V.
Synlett 2004, 558. (h) Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew.
Chem., Int. Ed. 2004, 43, 476. (i) Chowdari, N. S.; Suri, J. T.; Barbas, C.
F., III. Org. Lett. 2004, 6, 2507.
(1) For recent reviews on organocatalysis, see: (a) Dalko, P. L.; Moisan, L.
Angew. Chem., Int. Ed. 2004, 43, 5138. (b) Berkessel, A.; Gro¨ger, H.
Asymmetric Organocatalysis; WCH: Weinheim, Germany, 2004. (c)
Seayed, J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (d) Jarvo, E. R.;
Scott, J. M. Tetrahedron 2002, 58, 2481. (e) List, B. Tetrahedron 2002,
58, 5573. (f) List, B. Synlett 2001, 11, 1675. (g) See also: Acc. Chem.
Res. 2004, 37, number 8. Special edition devoted to asymmetric organo-
catalysis.
(2) For recent accounts, see: (a) Notz, W.; Tanaka, F.; Barbas, C. F., III. Acc.
Chem. Res. 2004, 37, 580. (b) List, B. Acc. Chem. Res. 2004, 37, 548. (c)
Co´rdova, A. Acc. Chem. Res. 2004, 37, 102.
(3) (a) Bøgevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2002, 41, 1790. (b) List, B. J. Am. Chem.
Soc. 2002, 124, 5656. (c) Vogt, H.; Vanderheiden, S.; Brase, S. Chem.
Commun. 2003, 2448. (d) Suri, J. T.; Steiner, D. D.; Barbas, C. F., III.
Org. Lett. 2005, 7, 3885. (e) Chowdari, N. S.; Barbas, C. F., III. Org. Lett.
2005, 7, 867. (f) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J. Am.
Chem. Soc. 2004, 126, 11770.
(4) For fluorination, see: (a) Steiner, D. D.; Mase, N.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2005, 44, 3706. (b) Beeson, T. D.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2005, 127, 8826. (c) Enders, D.; Hu¨ttl, M. R. M. Synlett
2005, 991. (d) Marigo, M.; Fielenbach, D.; Braunton, A.; Kjærsgaard, A.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 3703. For chlorination,
see: (e) Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2004, 126, 4108. (f) Halland, N,; Braunton, A.; Bachmann, S.; Marigo,
M.; Jørgensen, K. A. J. Am. Chem. Soc. 2004, 126, 4790. For bromination,
see: (g) Bertelsen, S.; Halland, N.; Bachmann, S.; Marigo, M.; Braunton,
A.; Jørgensen, K. A. Chem. Commun. 2005, 4821.
9
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J. AM. CHEM. SOC. 2005, 127, 18296-18304
10.1021/ja056120u CCC: $30.25 © 2005 American Chemical Society

Organocatalyst for
R
-Functionalization of Aldehydes
A R T I C L E S
Scheme 1. Highly Enantioselective R-Functionalizations of Aldehydes Catalyzed by the R,R-Diarylprolinol Silyl Ether
fluorination,4b and aldol reactions of aldehydes.9 However, for
both proline and the MacMillan catalyst, good hydrogen-bonding
properties of the electrophiles are in many cases proposed to
be important to achieve high asymmetric induction.10
To overcome these limitations connected with the mechanism
of chiral induction associated with proline, the strategy was to
design a pyrrolidine derivative able to induce high enantiose-
lectivities by controlling the geometry of the enamine and
through efficient face shielding.
We therefore set out to develop an organocatalyst that could
be suitable for a large variety of transformations as well as new
enantioselective reactions that are not efficiently catalyzed by
proline and other common organocatalysts. In this article we
present the development of the R,R-diarylprolinol silyl ether as
a general catalyst for R-functionalization of aldehydes. We have
previously communicated the use of this catalyst for the
stereogenic formation of C-F4d and C-S5 bonds, and now we
will demonstrate the generality of the catalyst to be also highly
efficient for different asymmetric reactions, such as the stereo-
genic formation of C-C, C-N, and C-Br bonds, with good
to high yields and with excellent enantioselectivities (Scheme
1). Furthermore, we will present mechanistic insight into the
reaction course applying nonlinear effect studies, kinetic resolu-
tion, and computational studies leading to an understanding of
the properties of the R,R-diarylprolinol silyl ether catalyst and
to justify both the high enantioselectivity and the broad scope
of the catalyst.
Our investigations started from a careful survey of a large
set of experiments carried out by our and other groups involved
in organocatalytic processes, and two related structures attracted
our attention (Figure 1).
Figure 1.
(S)-2-(Diphenylmethyl)-pyrrolidine ((S)-1) is often found to
be a very active catalyst for a variety of transformations, but
only in few cases high enantioselectivities are obtained.11 On
the other hand, (S)-2-diphenyl-prolinol ((S)-2a) often promoted
reactions with a good level of stereocontrol, but the processes
are characterized by a low catalyst turnover.12 This behavior
has been partially attributed to the increased size of the
substituent. Our working hypothesis was that the relatively small
size of the hydroxyl group could not justify such a large decrease
of reactivity. Instead, we ascribed the low catalyst turnovers
observed for the pyrrolidine derivative (S)-2a, mainly to the
formation of the relatively stable and unreactive hemiaminal
species A and B that remove a significant amount of catalyst
(S)-2a from the catalytic cycle (Scheme 2).13
To prevent the proposed hemiaminal formation, the hydroxyl
group was protected with a TMS group [eq 1]. Among the many
possible protecting groups, the TMS group was chosen because
the TMS-protected catalyst can be prepared in one single step
starting from the corresponding prolinol. This simple modifica-
tion of (S)-2 to (S)-3 drastically increased the catalytic turnover
in the R-functionalization of aldehydes (vide infra).
Results and Discussions
Catalyst Design. The high efficiency, in terms of both
reactivity and enantioselectivity often observed with proline, is
ascribed to the dual activation of both the nucleophilic aldehyde
and the electrophile.10 This means that the approach of the
electrophile to the enamine intermediate is controlled by
hydrogen bonding to the carboxylic acid function of proline
and not by steric shielding. Consequently, proline is usually
not an efficient catalyst in terms of enantioselectivity for
reactions of aldehydes with electrophiles that are poor hydrogen-
bond acceptors.
(9) Mangion, I. K.; Northrup, A. B.; MacMillan, D. C. W. Angew. Chem., Int.
Ed. 2004, 43, 6722.
(10) (a) Allemann, C.; Gordillo, R.; Clemente, F. R.; Cheong, P. H.; Houk, K.
N. Acc. Chem. Res. 2004, 37, 558. (b) Cheong, P. H.-Y.; Houk, K. N. J.
Am. Chem. Soc. 2004, 126, 13912. (c) Bahmanyar, S.; Houk, K. N. Org.
Lett. 2003, 5, 1249. (d) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc.
2001, 123, 11273.
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A R T I C L E S
Franze´n et al.
Scheme 2. Catalytic Cycle with Formation of Unreactive Hemiaminal Species A and B that Remove a Significant Amount of Catalyst (S)-2a
from the Catalytic Cycle
Table 1. Organocatalyzed Enantioselective R-Amination of
Aldehydesa
Further improvements in enantioselectivity were made through
the variation of the aryl substituents in the catalyst structure,
and the trifluoro derivative (S)-3c was identified as the best
catalyst for a series of transformations (Scheme 1). It is
important to note that the excellent results summarized in
Scheme 1 are for both addition and substitution reactions and
also for electrophiles not having hydrogen-bond capability.
entry
aldehyde
R
R
′
product
yieldb [%]
eec [%]
1
2
3
4a
4b
4b
4c
4d
Et
Et
Et
i-Pr
Et
6a
6b
6c
6d
6e
79
88
73
83
81
90
97
92
97
92
i-Pr
i-Pr
t-Bu
allyl
4
Catalyst Survey. A. R-Amination of Aldehydes. The direct
R-amination of aldehydes was independently developed by List3b
and our group3a as an effective strategy for the formation of
optically active amino alcohols and amino acid derivatives using
L-proline as the catalyst. With the trifluoro substituted catalyst
(S)-3c in hand we decided to investigate if this catalyst could
match up with the high standards set by proline.
5d
Et
a Compound 5 (0.25 mmol) was added to 4 (0.30 mmol) and (S)-3c (0.025
mmol) in CH2Cl2 (0.5 mL) at room temperature. b Yield of isolated product.
c The ee value was determined by chiral GC on the corresponding
oxazolidinones. d Reaction performed at -15 °C.
ee vs 93% ee for 6b and 97% ee vs 91% ee for 6d); and (iii)
reactions catalyzed by (S)-3c proceed faster.
The results achieved with the R,R-diarylprolinol silyl ether
(S)-3c matches those obtained with L-proline and smoothly
catalyzed the reaction between aldehydes 4 and azodicarboxy-
lates 5 in CH2Cl2 at room temperature [eq 2]. The R-aminated
products 6a-e were isolated in high yields and with 90-97%
ee as the corresponding oxazolidinones after reduction of the
aldehyde moiety and subsequent cyclization (Table 1). A
comparison of the results obtained using the two alternative
catalytic systems, reveals the following important differences:
(i) the absolute configuration of the aminated product obtained
with (S)-3c is opposite to the configuration obtained with
L-proline, although the absolute configuration of the catalysts
is the same (vide infra); (ii) some of the products are obtained
with higher enantiomeric excess using catalyst (S)-3c (e.g., 97%
B. Mannich Reactions. The Mannich reaction is a classic
method for the preparation of R-amino aldehydes.2c The
L-proline catalyzed Mannich reaction of unmodified aldehydes
with a N-PMP-protected R-imino ethyl glyoxylate to give direct
access to highly functionalized R-amino acids has been thor-
oughly investigated mainly by Barbas et al.8
The application of catalyst (S)-3c (10 mol %) to this
transformation (eq 3) turned out to be successful as reported in
Table 2. Treatment of aldehydes 4a,b,d-f with the N-PMP-
(11) Juhl, K.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2003, 42, 1498.
(12) For some comparing studies on the reactivity between compound 1 and 2a
preformed within our group, see refs 4d, 4f, 5, 11, and 15d.
(13) (a) Zuo, G.; Zhang, Q.; Xu, J. Heteroat. Chem. 2003, 14, 42. (b) Okuyama,
Y.; Nakano, H.; Hongo, H. Tetrahedron: Asymmetry 2000, 11, 1193.
9
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Organocatalyst for
R
-Functionalization of Aldehydes
A R T I C L E S
Table 2. Organocatalyzed Enantioselective Mannich Reaction of
Table 3. Organocatalyzed Enantioselective Michael Addition of
Aldehydesa
Aldehydes to Methylvinyl Ketonea
entrya
aldehyde
R
product
yieldb [%]
eec [%]
entrya
aldehyde
R
product
yieldb [%]
dr
ee [%]
1
2
3
4a
4f
4g
Et
Me
n-Pr
10a
10b
10c
83
80
82
93
92
95
1
2
3
4
5
4a
4b
4d
4e
4f
Et
8a
8b
8c
8d
8e
83
79
63e
74
76
80:20
92:8
90:10
91:9
94c
98c
98d
94d
98c
i-Pr
allyl
Bn
a Compound 9 (0.25 mmol) was added to 4 (0.50 mmol) and (S)-3c (0.025
mmol) in EtOH (0.5 mL) at 40 °C and stirred for 64 h. b Yield of isolated
product. c The ee value was determined by chiral GC.
Me
86:14
a Compound 7 (0.25 mmol) was added to 4 (0.50 mmol) and (S)-3c (0.025
mmol) in CH3CN (0.5 mL) at room temperature. b Yield of isolated product.
c The ee value was determined by chiral HPLC. d The ee value was
determined by chiral HPLC after LiAlH4 reduction to the corresponding
diol. e Yield of the corresponding diol after LiAlH4 reduction.
highly stereoselective manner and all products 10a-c were
obtained in high yields (80-83%) and excellent enantiomeric
excesses (92-95% ee) using catalyst (S)-3c (eq 4 and Table
3). For this reaction the temperature had to be increased in order
to obtain a shorter reaction time. It is important to point out
that, even after these relatively long reaction times and the high
reaction temperature, only minor amounts of homo-aldol product
could be observed (<5%).
The (S)-3c catalyst improves the enantiomeric excess of the
Michael adducts significantly compared to the catalyst (based
on (S)-1) used in our initial study.15d For the Michael adducts
10a and 10b, we obtained 85% yield and 79% ee and 83% yield
and 64% ee, respectively, in our initial study, while catalyst
(S)-3c significantly improves the enantioselectivity to 93% and
92% ee, respectively, and with the same good yields (Table 3,
entries 1, 2). Recently, after our first reports on the catalytic
properties of O-protected diarylprolinol derivatives, Hayashi et
al.15b and Gellman et al.15a independently reported the successful
application of this type of catalysts in conjugated addition
reactions. It should be noted that the work by Hayashi et al.15b
extends the use of this class of catalysts to also include the
addition of aldehydes to nitroalkenes using (S)-3a.
D. R-Fluorination of Aldehydes. Several groups have
recently investigated the asymmetric R-halogenation of alde-
hydes, and MacMillan et al.4e and our group4f independently
reported the direct enantioselective R-chlorination of aldehydes.
This was shortly followed by the independent development of
enantioselective R-flourination of aldehydes by Barbas et al.,4a
MacMillan et al.,4b Enders et al.,4c and us.4d Our approach to
the asymmetric R-fluorination of aldehydes relied on N-
fluorobenzensulfonimide (NFSI) as the fluorination agent and
the disubstituted-diphenylprolinol silyl ether (S)-3c as the
catalyst,4d since the use of L-proline, L-proline amide, and (R,R)-
2,5-diphenylpyrrolidine all gave poor yields and enantioselec-
tivity. A screening showed that, with catalyst (S)-3c, high
asymmetric induction was obtained, and the choice of solvent
had only a minor effect on the selectivity. However, reactions
in CH2Cl2 and CH3CN gave only moderate conversions of, e.g.,
3-phenyl butanal 4b in the presence of 10 mol % of catalyst
(S)-3c and 1.2 equiv of NFSI. This was the result of the
desilylation of (S)-3c to give (S)-2c in the presence of NSFI.
We have found that (S)-2c shows very low catalytic activity,
and the low conversion was caused by inactivation of the
catalyst, in line with earlier discussions. However, an improve-
ment in stability of catalyst (S)-3c was observed in methyl-tert-
butyl ether (MTBE). Complete conversion of NFSI was
obtained, along with significant amounts of difluorinated
protected R-imino ethyl glyoxylate 7 in the presences of catalyst
(S)-3c at room temperature gave the Mannich adducts 8a-e
with very high enantioselectivies, 94-98% ee.
Investigation of the relative conformation between the two
stereocenters in the Mannich adducts 8 revealed that the reaction
proceeds with moderate to high anti-diastereoselectivity. It is
worthwhile to emphasizing the fact that the use of L-proline
leads to the opposite syn-diastereoisomer and this behavior is a
direct consequence of the different structure and properties of
the two catalysts leading to two different transition states (vide
infra). Attempts have been performed previously to promote
the anti-selective organocatalytic asymmetric Mannich reactions
with the same reagents.14 The application of (S)-2-methoxym-
ethylpyrrolidine as the catalyst (20 mol %) gave the anti-
diastereomer in moderate yields (44-68%) and enantioselec-
tivities in the range of 74-82% ee. The use of catalyst (S)-3c
leads to a significant improvement in terms of yield and
enantioselectivity: for entries 1 and 2 in Table 2, the results
with (S)-2-methoxymethylpyrrolidine were 44% yield, 1:1 dr,
75% ee and 52% yield, 10:1 dr, 82% ee, compared to 82% yield,
80:20 dr, 94% ee and 79% yield, 92:8 dr, 98% ee, respectively,
with catalyst (S)-3c.
C. Conjugate Additions to Methylvinyl Ketone. Conjugate
additions are reactions of fundamental importance in organic
chemistry, and chiral secondary amines have been shown to
catalyze the direct enantioselective Michael addition of alde-
hydes to vinyl ketones and nitrostyrene.15 The additions of
aldehydes to vinylmethyl ketone have previously been studied
in our group.15d It was found that pyrrolidine derivative (S)-1
was more reactive than prolinol (S)-2a; on the other hand,
prolinol (S)-2 provided considerably higher enantioselectivity
in the reaction than (S)-1, which is in line with the earlier
discussion (see above). Furthermore, in this reaction proline gave
very low conversion and only 20% ee. We were pleased to find
that aldehydes 4a,f-g reacted with methylvinyl ketone 9 in a
(14) Co´rdova, A.; Barbas, C. F., III. Tetrahedron Lett. 2002, 43, 7749.
(15) (a) Chi, Y.; Gellman, S. H. Org. Lett. 2005, 7, 4253. (b) Hayashi, Y.; Gotoh,
H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (c) Wang,
W.; Wang, J.; Li, H. Angew. Chem., Int. Ed. 2005, 44, 1369. (d) Melchiorre,
P.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 4151. (e) Betancort, J. M.;
Barbas, C. F., III. Org. Lett. 2001, 3, 3737. (f) Mase, N.; Thayumanavan,
R.; Tanaka, F.; Barbas, C. F., III. Org. Lett. 2004, 6, 2527. (g) Betancort,
J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.; Barbas, C. F., III.
Synthesis 2004, 1509. (h) Hechavarria Fonseca, M. T.; List, B. Angew.
Chem., Int. Ed. 2004, 43, 3958. (i) Peelen, T. J.; Chi, Y.; Gellman, S. H.
J. Am. Chem. Soc. 2005, 127, 11598.
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A R T I C L E S
Franze´n et al.
Table 4. Organocatalyzed Enantioselective R-Fluorination of
advantages, such as easier synthesis of the catalyst and no need
for mixed solvents and additives such as benzoic acid and water.
Furthermore, (S)-3c uniformly gives excellent enantioselectivi-
ties of the optically active R-bromo alcohols 14a-c, while (R,R)-
2,5-diphenylpyrrolidine4g gave enantioselectivies from 65% ee
and up.
Aldehydesa
F. R-Sulfenylation of Aldehydes. Catalyst (S)-3c is also a
very effective catalyst for the direct asymmetric R-sulfenylation,5
and before our report, all practical methods for preparation of
chiral R-sulfenylated aldehydes have been multistep procedures
that involve chiral auxiliaries.16 According to our knowledge,
no catalytic processes are available for the preparation of these
optically active sulfur compounds. For the direct R-sulfenylation
of aldehydes, several challenges emerged with regard to
sulfenylating reagent, such as the sulfur protecting and leaving
groups. A careful screening showed that compound 15, having
triazole as the leaving group, gives access to the benzyl protected
thiol functionality and fulfilled the requirement for being the
optimal sulfenylating agent.5
conv to
entry
aldehyde
R
11b [%]
product
yieldc [%]
eed [%]
1
2
3
4
5e
6
7
8
4c
4e
4g
4h
4i
4j
4k
4l
t-Bu
Bn
n-Pr
n-Bu
>95
>90
>95
>90
12a
12b
12c
12d
12e
12f
97
93
96
91
96
96
96
91
74
n-Hex
1-Ad
55
75
69
64
Cy
12g
12h
(CH2)3OBn
In analogy to other reactions previously studied, catalyst (S)-
2a was completely inactive while catalyst (S)-1 promoted the
formation of the desired product in good yield, but with low
enantiomeric excess due also to the racemization of the optically
active sulfenylated aldehydes in the reaction mixture. The R,R-
diarylprolinol silyl ether (S)-3c turned out to be an effective
catalyst for the R-sulfenylation of simple aldehydes (eq 7), and
the results are summarized in Table 6.
Substrates having a small (Me) or bulky (t-Bu) substituent
were consistently converted into products 17 with 95-98% ee.
The newly functionalized aldehydes racemize on silica, and the
products were isolated after in situ reduction with NaBH4 to
the corresponding optically active alcohol 17a-f. Very recently,
several attempts were carried out to perform direct organocata-
lytic enantioselective R-sulfenylation and selenenylation reac-
tions of adehydes.17 For the direct R-sulfenylation, a large
number of organocatalysts, such as L-proline, L-proline amide,
and pyrrolidine trifluoromethanesulfonamide, as well as other
chiral amines, were tested using N-(phenylthio)phthalimide as
the sulfenylating reagent. However, no enantiomeric excess was
reported. The related R-selenenylation of both aldehydes and
ketones were also studied with L-proline amide and pyrrolidine
trifluoromethanesulfonamide as the catalysts and N-(phenylse-
leno)phthalimide as the selenenylation reagent, and low enan-
tioselectivity was reported for this transformation.
a NFSI (0.25 mmol) was added to 4 (0.375 mmol) and (S)-3c (0.0025
mmol) in TBME (0.5 mL) at room temperature. b Conversion determined
by GC. c Yield of the respective alcohol obtained by reduction with NaBH4.
d The ee value was determined by CP-GS on the aldehydes or by chiral
HPLC on the alcohol or alcohol derivative. e 1.1. equiv of NFSI; 1 equiv
of aldehyde.
aldehydes. Further optimization of the reaction conditions
revealed that decreasing the catalyst amount to only 1 mol %
and using a slight excess of aldehyde gave higher yields
maintaining the high enantiomeric excess. The corresponding
optically active fluoro alcohols 12a-h could be isolated in
moderate to high yields and excellent enantioselectivity (91-
97% ee) after NaBH4 reduction (eq 5 and Table 4).
As mentioned above several papers were published within a
few weeks describing the organocatalyzed enantioselective
R-fluorination of aldehydes.4a-d A comparison of the properties
of catalyst (S)-3c with the imidazolidinone catalyst used by both
Barbas et al.4c and MacMillan et al.4b shows that both systems
give excellent enantioselectivity. However, higher catalytic
activity of (S)-3c leads to shorter reaction times. The higher
reaction rate observed using (S)-3c allows a lower catalytic
loading (0.25 to 1 mol %), while the imidazolidinone system
required 2.5 to 100 mol %.
E. R-Bromination of Aldehydes. The direct R-halogenation
reactions developed by our group have been further advanced
to include also the enantioselective R-bromination of aldehydes
using the C2-symmetric (R,R)-2,5-diphenylpyrrolidine as the
catalyst.4g We were pleased to find that when a selection of
aldehydes 4b,c,j were treated with 4,4-dibromo-2,6-di-tert-butyl-
cyclohexa-2,5-dienone 13 in the presence of catalyst (S)-3c in
CH2Cl2 at -24 °C, a smooth R-bromination occurred with
excellent asymmetric induction (eq 6 and Table 5). The
corresponding optically active bromo alcohols 14a-c could be
isolated after NaBH4 reduction in high yields.
The low temperature was necessary only to prevent undesired
side reactions such as bromination of the catalyst. At 0 °C the
corresponding reaction stopped after 30% conversion, whereas
at -24 °C full conversion was obtained after 90 min with the
same enantiomeric excess for the optically active R-bromo
alcohol. Compared to the use of (R,R)-2,5-diphenylpyrrolidine4g
as the catalyst for the R-bromination, catalyst (S)-3c has several
Mechanistic Insights
Control of Enantioselectivity through Control of Enamine
Geometry. In the transition state, the conjugation of the lone-
pair electrons of the nitrogen atom with the double bond restricts
the number of possible conformations of the reactive enamine
intermediate (Scheme 3).
(16) For examples: (a) Youn, J.-H.; Herrmann, R.; Ugi, I. Synthesis 1987, 158.
(b) Poli, G.; Belvisi, L.; Manzoni, L.; Scolastico, C. J. Org. Chem. 1993,
58, 3165. (c) Enders, D.; Scha¨fer, T.; Piva, O.; Zamponi, A. Tetrahedron
1994, 50, 3349. (d) Chibale, K.; Warren, S. Tetrahedron Lett. 1994, 35,
3991. (e) Enders, D.; Scha¨fer, T.; Mies, W. Tetrahedron 1998, 54, 10239.
(f) Evans, D. A.; Campos, K. R.; Tedrow, J. S.; Michael, F. E.; Gagne´, M.
R. J. Am. Chem. Soc. 2000, 122, 7905. See also: (g) Jereb, M.; Togni, A.
Org. Lett. 2005, 7, 4041.
(17) (a) Wenig, W.; Li, H.; Wang, J.; Liao, L. Tetrahedron Lett. 2004, 45, 8229.
(b) Wang, W.; Wang, J.; Li, H. Org. Lett. 2004, 6, 2817. (c) Wang, J.; Li,
H.; Mei, Y.; Lou, B.; Xu, D.; Xie, D.; Guo, H.; Wang, W. J. Org. Chem.
2005, 70, 5678.
9
18300 J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005

Organocatalyst for
R
-Functionalization of Aldehydes
A R T I C L E S
Figure 2. DFT-optimized structure of the enamine formed by 3-methyl butanal (4b) and catalyst (S)-3c.
Table 5. Direct Organocatalyzed Enantioselective R-Bromination
Scheme 3. Enamine Intermediate Conformations
of Aldehydesa
calculations of the optimized enamine intermediate using a
6-31G* basis set.18 The energetically lowest intermediate
structure shows that one of the 3,5-trifluoromethyl phenyl groups
efficiently covers the Re-face of the enamine (Figure 1). As a
consequence, the electrophilic attack must occur from the Si-
face providing the excellent enantioselectivities (Figure 2).
The absolute configuration of the products has been found
to be identical for all the products and in agreement with the
model proposed.19 It is interesting to note that catalyst (S)-3c
and L-proline that have identical absolute configurations,
however, due to the different nature of the transition state, in
the case of amination reaction and Mannich reaction, promote
the formation of products with the opposite absolute configu-
ration at the R-carbon stereocenter (Scheme 4).
entry
aldehyde
R
product
yieldb [%]
eec [%]
1
2
3
4b
4c
4j
i-Pr
t-Bu
Adm
14a
14b
14c
74
71
74
94
95
95
a Compound 13 (0.37 mmol) was added to 4 (0.25 mmol) and (S)-3c
(0.025 mmol) in CH2Cl2 (0.5 mL) at -24 °C and stirred for 90 min.
b Isolated yield. c The ee value was determined by chiral GC. d The ee value
was determined by chiral HPLC after m-nitrobenzoylation of 14c.
Table 6. Organocatalyzed Enantioselective R-Sulfenylation of
Aldehydesa
Scheme 4. Transition-State Models for L-Proline and
R,R-Diarylprolinol Silyl Ether (S)-3c Catalyzed R-Amination of
Aldehydes
entry
aldehyde
R
product
yieldb [%]
eec [%]
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
Et
17a
17b
17c
17d
17e
17f
85
81
83
64
94
60
96
98
97
96
97
95
i-Pr
t-Bu
Allyl
Bn
Effect of Catalyst Structure on the Enantioselectivity of
the Reactions. The effect of the structure of the aromatic groups
of the prolinol derivative on the enantiomeric excess of the
product has been investigated for the R-sulfenylation of 3-methyl
butanal. The experiments were carried out varying the R-
substituent on the aromatic groups in the catalyst (see eq 1).
The enantiomeric excess was found to be increasing when
moving from the simple diphenyl-prolinol ((S)-3a) to 3,5-
dimethyl ((S)-3b) and 3,5-ditrifluoromethyl ((S)-3c) substitution
Me
a Compound 15 (0.33 mmol) was added to 4 (0.25 mmol) and (S)-3c
(0.025 mmol) in toluene (0.5 mL) at room temperature. b Yield of the
respective alcohol obtained by reduction with NaBH4. c The ee value was
determined by chiral HPLC on the alcohol or other derivatives.
The E-conformation (b) is energetically favored over the
Z-conformation (a), and the bulky substituent on the R-position
of the pyrrolidine ring raises the energy of the conformation
(c). The large aryl and silyl substituents of the catalyst (S)-3c
can efficiently shield the Re-face of the favored E-configuration
of the enamine.
(18) (a) Frisch, M. J. et al. Gaussian 98, revision A.7; Gaussian, Inc.: Pittsburgh,
PA, 1998. (b) Frisch, M. J. et al. Gaussian 03, revision B.05; Gaussian,
Inc.: Pittsburgh, PA, 2003.
(19) The absolute configuration was determined by comparison of optical rotation
with literature data. See Supporting Information for references.
This hypothesis is confirmed by a model based on DFT
9
J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005 18301

A R T I C L E S
Franze´n et al.
Scheme 5. Explanation to the Configurative Stability of R-Functionalized Aldehydes
Table 7. Relation between Taft’s Es Values of the Aromatic
Substituents of (S)-3 and Enantioselectivity in the R-Sulfenylation
of 3-Methyl Butanala
Scheme 6. Explanation to the Configurative Stability of
R-Fluorinated Aldehydes
Taft’s Es
entry
R
values
eeb [%]
1
2
3
H
CH3
CF3
0
77
90
98
-1.24
-2.40
a Compound 15 (0.27 mmol) was added to 4b (0.25 mmol) and (S)-3c
(0.025 mmol) in toluene (0.5 mL) at ambient temperature for 3 h. b The ee
value was determined by chiral GC.
(Table 7), indicating that the electronic properties of the R-group
in the catalyst have no effect on the enantiomeric excess.
Taft’s Es values,20 which are steric substituent constants, are
in approximately linear correlation with the optical activity of
the products (Table 7). The size of CF3 is relatively large, in
the order of Me < i-Pr < CF3 < t-Bu and, hence, in sharp
contrast to the small van der Waal radius of fluorine.21 This
supports that the asymmetric induction observed with catalyst
(S)-3c completely relies on selective enamine conformation and
steric shielding.
Conformational Stability of the Products (Thermody-
namic and Kinetic). The stability of the chiral center of the
product is as important as its enantioselective formation, and
the structure of the catalyst (S)-3c is also suited to prevent this
undesired path.
The racemization of the R-functionalized aldehydes is in
general prevented because of the higher energy of the enamine
species with the more sterically demanding disubstitued alde-
hyde, thus leading in preference to iminium-ion hydrolysis and
release of the product (Scheme 5).
This explanation is not sufficient in the case of R-fluorinated
aldehydes because of the small steric interaction of the fluorine
atom. The van der Waal radius of the fluorine atom (1.35 Å) is
in fact not much larger than the van der Waal radius of the
hydrogen atom (1.20 Å). The configurational stability is even
more surprising because a significant amount of difluorinated
product has been observed. In fact, both processes, racemization
and difluorination, pass through the same enamine intermediate.
The complex system that leads to the formation of highly
optically active products in the fluorination reaction is shown
in Scheme 6.
In the preferably formed (S,S)-19 iminium ion, the remaining
R-hydrogen atom (shown in bold red) is covered by the shielding
substituents on the catalyst. The geminal fluorine atom and the
substituents on the pyrrolidine ring are presumably forming a
hydrophobic pocket that protects the remaining acidic R-proton
from abstraction by water and prevents racemization through
enamine formation. For that reason, the nucleophilic attack of
water will more easily take place at the carbon atom of the
iminium ion releasing the R-fluorinated aldehyde and thereby
closing the catalytic cycle. The opposite situation is presumed
in the formation of the disfavored iminium-ion intermediate
(R,S)-19 where the remaining R-hydrogen atom is not shielded,
consequently resulting in a fast enamine formation and subse-
quent racemisation or difluorination.
(20) (a) Taft, R. W., Jr. J. Am. Chem. Soc. 1952, 74, 2729. (b) Taft, R. W., Jr.
J. Am. Chem. Soc. 1952, 74, 3120. (c) Taft, R. W., Jr. J. Am. Chem. Soc.
1953, 75, 4231.
(21) (a) de Riggi, I.; Virgili, A.; de Moragas, M.; Jaime, C. J. Org. Chem. 1995,
60, 27. (b) Wolf, C.; Ko¨nig, W. A.; Roussel, C. Liebigs Ann. 1995, 781.
In Figure 3 is reported the calculated structure for the
iminium-ion intermediate formed after R-fluorination, (S,S)-19
and (R,S)-19.
9
18302 J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005

Organocatalyst for
R
-Functionalization of Aldehydes
A R T I C L E S
Figure 3. DFT-optimized structures of the iminium-ion intermediate (S,S)-19 and (R,S)-19.
Figure 4. NFSI (0.27 mmol) was added to 4e (0.25 mmol) and the appropriate mixture of (S)-3c and (R)-3c (0.025 mmol) in MTBE (0.5 mL) at ambient
temperature and enantiomeric excess, and conversion was determined by GP-GC.
The energetically lowest intermediate structures show that
the 3,5-trifluoromethyl phenyl groups and the TMS group
efficiently shield the R-proton in (S,S)-19, thereby protecting it
from abstraction preventing enamine formation. On the other
hand, for the diastereoisomer (R,S)-19, the R-proton is placed
in the open face and is more accessible toward abstraction.
A direct implication of our hypothesis is that the catalytic
system developed should be able to differentiate between the
two enantiomers of the monofluorinated product and promote
the kinetic resolution of racemic R-fluoro aldehydes.
In fact, a racemic mixture of R-fluoro aldehyde 12b was
slowly converted to the difluorinated product 21 in the presence
of 0.5 equiv of NFSI and 1 mol % of catalyst (S)-3c (eq 8).
After 20% conversion to 21 (4 h reaction time), 20% ee of
R-fluoro aldehyde (S)-12b was found. The experiment clearly
revealed that (R)-12b was consumed faster than (S)-12b.
was subjected to the standard reaction conditions, and in Figure
4a is shown the relation between the enantiomeric excess of
the monofluorinated product and the enantiomeric excess. The
nonlinear effect observed is in agreement with a postulated
hydrophobic pocket and with the described kinetic resolution
of 12b. When catalyst (S)-3c is used in excess, relative to (R)-
3c, the minor amount of (R)-12b formed is quickly difluorinated
to give 21 in the presence of the relatively large amount of (S)-
3c. At the same time, the difluorination of (S)-12b proceeds at
a much lower rate, because it can be catalyzed only by the small
amount of (R)-3c present in the reaction mixture. Therefore the
enantiomeric excess of (R)-12b over (S)-12b is higher than
expected.
The effect of the optical purity of the catalyst on the
conversion of the aldehyde 4e to the mono- (12b) and
difluorinated (21) products in the presence of NFSI and catalyst
(S)-3c was also studied (Figure 4b). It was observed that when
the enantiomeric excess of the catalyst was increased the amount
of difluorination product decreased. This is another conformation
of our hypothesis since catalyst (S)-3c mainly promotes the
difluorination of the optically active product obtained in the
presence of catalyst (R)-3c and vice versa, and it was reasonable
to expect the largest amount of difluorinated product 21 when
racemic 3c is used.
To have an enhanced understanding of the process under
study, we planned a new set of experiments. The aldehyde 4e
9
J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005 18303

A R T I C L E S
Franze´n et al.
Table 8. Effect of Solvent and Temperature on Enantioselctivity
and Conversion in the Michael Addition of Butanal 4a to
Methylviny Ketone 9 Catalyzed by (S)-3c after 48 h Reaction
Timea
Catalyst (S)-3c has been mixed with 3-methyl butanal under
standard reaction conditions (0.5 M and ambient temperature).
Experiments in CD3OD, CD3CN, CDCl3, CD2Cl2, and CD3S-
(O)CD3 revealed that between 55% and 70% of the catalyst
has reacted with the aldehyde to form the enamine species.
conversion
to 10ab [%]
entry
solvent
temp [
°
C]
eec [%]
1
2
3
4
5
6
7
DCE
40
40
40
40
20
60
60
17
11
6
72
30
58
90
96
97
95
96
96
93
88
Conclusions
TBME
CH3CN
EtOH
EtOH
EtOHd
EtOH
We have demonstrated that the R,R-diarylprolinol silyl ether
(S)-3c is able to catalyze R-amination, fluorination, bromination,
and sulfenylation of aldehydes, as well as Mannich and Michael
addition reactions, and herein we present the preparation of 30
different compounds with 90-98% ee from achiral precursors.
It has also been shown by interpretation of experimental data,
calculations, and kinetic studies that the high asymmetric
induction obtained with catalyst (S)-3c is an effect of highly
efficient face-shielding and a fixed geometry of the reactive
enamine intermediate. Furthermore, when using catalyst (S)-3c
a high conformational stability of the products is observed as a
result of the proposed hydrophobic pocket that protects the
product from racemisation. This catalytic system is extremely
flexible, since solvents and temperature influence only the yields
and not the enantioselectivities of the reactions. Recently, we
also demonstrated that catalyst (S)-3c was capable of iminium-
ion activation with high stereoselectivity.22 Further investigations
of the capacity of this catalyst toward new reactions are currently
under investigation in our laboratory and results from these
studies will be presented in the future.
a Compound 9 (0.25 mmol) was added to 4a (0.50 mmol) and (S)-3c
(0.025 mmol) in the appropriate solvent (0.5 mL) and at the appropriate
temperature for 44 h. b Conversion determined by H NMR experiments.
1
c The ee value was determined by chiral GC. d 20 h reaction time.
Solvent and Temperature Effect. A large advantage of the
use of the newly developed R,R-diarylprolinol silyl ether (S)-
3c is that the high enantioselectivities are the result of efficient
shielding and the fixed geometry of the enamine intermediate.
A consequence of this fact is that the choice of the solvent and
temperature can be used to modulate the reactivity but has only
a minor effect on the enantioselectivity. For example, the
Michael addition of butanal 4a to methylvinyl ketone 9 catalyzed
by (S)-3c was screened (eq 4) for a series of solvents and
conversion and enantioselectivity were determined after 48 h
at 40 °C (Table 8). It was found that EtOH gave the highest
conversion, although, for the four solvents compared, there is
no effect on the stereoselectivity of the reaction.
The stability of the system was further demonstrated by
increasing the temperature further, and at 60 °C for 24 h 60%
conversion and 93% ee were obtained. After 48 h at 60 °C
almost full conversion was observed together with a decrease
of enantiomeric excess to 88%, most likely due to racemisation
of the product. However, for very reactive electrophiles, i.e.,
diethyl azodicarboxylates, an increase in enantiomeric excess
(from 86% to 92% ee) was observed when decreasing the
temperature from 20 to -15 °C for the amination of 4-pentenal
(Table 1, entry 5). It is also important to point out for the
Michael addition reaction that, even at 60 °C for 48 h, only a
minor amount of homo-aldol product could be observed
(<10%). Furthermore, in contradiction to proline, the pyrrolidine
derivative is soluble in all the common solvents but only
partially soluble in the more polar EtOH, DMF, and DMSO.
Acknowledgment. This work was made possible by a grant
from The Danish National Research Foundation. J.F. thanks The
Wenner-Gren Foundation for a grant, and M.M. and T.C.W.
thank EU: HMPT-CT-2001-00317 for financial support.
Supporting Information Available: Complete experimental
procedures and computational methods. Enantiomeric separation
conditions, spectral data, and optical rotation for all new
compounds. Complete ref 18. This material is available free of
charge via the Internet at http://pubs.acs.org.
JA056120U
(22) (a) Marigo, M.; Franze´n, J.; Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A.
J. Am. Chem. Soc. 2005, 127, 6964. (b) Marigo, M.; Schulte, T.; Franze´n,
J.; Jørgensen K. A. J. Am. Chem. Soc. 2005, 127, 15710.
9
18304 J. AM. CHEM. SOC. VOL. 127, NO. 51, 2005