How to make five contiguous stereocenters in one reaction: Asymmetric organocatalytic synthesis of pentasubstituted cyclohexanes

Article abstract of DOI:10.1002/anie.200704454

(Chemical Equation Presented) Give me five! An organocatalyzed two-component domino reaction has been developed in which two new C-C bonds and five stereocenters are created in a one-pot fashion (see scheme; DABCO = 1,4-diazabicyclo[2.2.2]octane, TMS = trimethylsilyl). The striking features of this transformation are the high preference for one diastereomer (out of 32 possible isomers) and enantioselectivities of up to 94 %.

Full text of DOI:10.1002/anie.200704454

Communications
DOI: 10.1002/anie.200704454
Asymmetric Organocatalysis
How to Make Five Contiguous Stereocenters in One Reaction:
Asymmetric Organocatalytic Synthesis of Pentasubstituted
Cyclohexanes**
Efraím Reyes, Hao Jiang, Andrea Milelli, Petteri Elsner, Rita G. Hazell, and
Karl Anker Jørgensen*
Asymmetric synthesis of complex molecules containing
multiple stereocenters is a well-known research area used
for the synthesis of a variety of natural products and other
molecules of interest.[1] In this field, strategies which reduce
the number of chemical steps for the final assembly of the
desired products are highly demanded, thereby decreasing the
formation of waste products and increasing the economy of
the processes.[2] One of the most important goals in this area is
the generation of more than one bond in a multistep reaction
concomitant with the creation of multiple stereocenters in a
one-pot fashion.[1] Recently, asymmetric one-pot syntheses of
complex organic molecules have been achieved with the
generation of up to eight new stereocenters by employing
different methodologies.[3] In the field of organocatalysis,
Enders et al. have performed the synthesis of substituted
cyclohexenes by applying a three-component domino reac-
tion,[3a] and Hayashi et al. have described a two-component
multistep Michael/Henry sequence for the synthesis of
cyclohexane derivatives by using pentane-1,5-dial and 2-
substituted nitroalkenes.[3c] To the best of our knowledge, the
generation of five or more stereocenters by one intermolec-
ular reaction of two compounds in an asymmetric fashion has
not so far been reported.
active cyclohexanols. Furthermore, this reaction represents
one of the few examples of organocatalytic conjugate addition
of nitroalkanes to a,b-unsaturated aldehydes.[3a,6a,b]
Our studies started with the discovery of a novel nitro-
Michael[6]/Henry[7] reaction promoted by a 1,3-dinucleo-
phile.[8] This transformation allows the straightforward syn-
thesis of pentasubstituted cyclohexanes in a one-pot fashion.
In the reaction between aldehyde 1a and dinitroalkane 2a, in
the presence of (S)-2-[bis(3,5-bistrifluoromethylphenyl)(tri-
methylsilyloxymethyl)]pyrrolidine (3a),[9] we observed that
the initially formed Michael adduct cyclized in situ to furnish
the cyclohexanol derivative 4a as the only product
(Scheme 1).
Scheme 1. Reaction of 2-pentenal 1a with the 1,3-dinitroalkane 2a in
the presence of the catalyst 3 and an external base. DABCO=1,4-
diazabicyclo[2.2.2]octane, TMS=trimethylsilyl, TES=triethylsilyl,
TBDMS=tert-butyldimethylsilyl.
In the course of our efforts to develop organocatalytic
methodologies to gain rapid access to complex molecules, we
recently achieved the synthesis of cyclohexenals containing
three contiguous stereocenters in good yields and excellent
stereoselectivities by using a multicomponent reaction.[4] In
fact, it has been demonstrated with this and other examples[5]
that organocatalysis can be a very valuable tool for control-
ling diverse asymmetric syntheses. Herein we describe the
first one-pot asymmetric formation of five stereocenters by an
intermolecular two-component reaction, which leads in this
particular case to the formation of highly substituted optically
During the screening of this reaction, we discovered a low
dependence on the solvent used and in all cases obtained
good stereoselectivities (1 major out of 32possible stereoiso-
mers) (Table 1). In fact, in many of the solvents tested and in
the presence of DABCO as the base additive (Table 1,
entries 1–4), the major diastereoisomer could be isolated after
column chromatography in moderate yields with up to
80% ee.[10] The best enantioselectivities were obtained using
CH2Cl2 as the solvent. In these cases, the use of 10 mol% of
DABCO was found to be more efficient with respect to yield
and enantioselectivity (Table 1, entries 5 and 6). It is impor-
tant to note that no epimerization occurs during the
purification. The diastereomeric ratio determined by
1H NMR spectroscopic analysis of the crude reaction mixture
is maintained after isolation of the single isomers. The
reaction temperature was decreased to 48C to improve the
stereoselectivity of the process (Table 1, entry 7). However, it
was observed that decreasing the reaction temperature gave
no improvement in the enantioselectivity. Other catalysts
[*] Dr. E. Reyes, H. Jiang, A. Milelli, Dr. P. Elsner, Dr. R. G. Hazell,
Prof. Dr. K. A. Jørgensen
Danish National Research Foundation: Center for Catalysis
Department of Chemistry, Aarhus University
8000 AarhusC (Denmark)
Fax: (+45)8619-6199
E-mail: kaj@chem.au.dk
[**] This work was made possible by a grant from The Danish National
Research Foundation and OChem School. E.R. thanks the “Eusko
Jaurlaritza-Gobierno Vasco” for financial support (postdoctoral
fellowship).
Supporting information for thisarticle isavailable on the WWW
under http://www.angewandte.org or from the author.
9202
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 9202 –9205
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Take advantage of blue reference links
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

Angewandte
Chemie
Table 1: Screening of the organocatalytic nitro-Michael/Henry reaction
of a,b-unsaturated aldehyde 1a with dinitro compound 2a.[a]
Table 2: Scope of the organocatalytic nitro-Michael/Henry reaction.[a]
Entry
Solvent
3
Yield [%][b]
d.r.[c]
ee [%][d]
1[e]
2[e]
3[e]
4[e]
5[e]
6[g]
7[e,h]
8[g]
9[g]
10[g]
iPrOH
AcOEt
DMF
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3a
3a
3a
3a
3a
3a
3a
n.d.[f]
n.d.[f]
n.d.[f]
n.d.[f]
45 (74)
45
4:2:1
4:2:1
4:1:1
4:2:1
4:2:1
4:2:1
4:2:1
4:2:1
4:2:1
4:2:1
80
80
46
80
84
90
Entry 1 (R1)
2 (R2)
Yield [%][b]
d.r.[c]
ee [%][d]
23
89
1
2
3
4
5
6
1a (Et)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
4a: 45
4:2:1 90
3b[i]
3c[i]
3d[i]
n.d.[f]
41
À58[j]
1b (Me)
1c (n-Pr)
1d (iPr)
1e (nBu)
1 f
4b: 43 (61) 4:1:1
75
4:2:1 86
4d: 38 (60) 3:1:1 90
4:2:1 87
3:1:0 94
89
4c: 44
35
93
[a] The reaction wascarried out on a 0.2-mmol scale of 1a and 2a, using
20 mol% of the catalyst 3 and DABCO in a vial containing 0.25 mL of the
appropriate solvent. [b] Yield of the isolated major stereoisomer
(combined yield of the three stereoisomers). [c] Determined by NMR
spectroscopy of the reaction mixture. [d] Determined by HPLC on a chiral
stationary phase. [e] 20 mol% of DABCO was used. [f] Not determined.
[g] 10 mol% of DABCO wasuesd. [h] Reaction performed at 4 8C.
[i] 10 mol% of 3 was used. [j] The opposite enantiomer was obtained.
4e: 43
4 f: 56[e]
(CH2OTIPS)
7
8
9
1g (cis-C6H11) 2a (Ph)
1h (C7H16)
1a (Et)
4g: 52
4h: 50
4i: 48
4:2:1 86
4:2:1 87
4:2:1 92
2a (Ph)
2b (p-
MeOC6H4)
2b (p-
MeOC6H4)
2c (m-
10[f] 1d (iPr)
4j: 53
4k: 65
5:1:1
89
11
1d (iPr)
12:2:3 90
(3b–d) were also tested for this transformation. It should be
noted that derivative 3b with a free OH group led to the
formation of the opposite enantiomer (Table 1, entry 8). This
is one of the first examples where opposite induction has been
observed using the pair of catalysts 3a and 3b.[6b] This result
can be rationalized by a possible hydrogen-bonding inter-
action between the free OH group of catalyst 3b and the
incoming dinitro compound. The more bulky substituted
pyrrolidine catalysts 3c and 3d also gave good enantioselec-
tivities (Table 1, entries 9 and 10). However, the yield
observed in these cases showed that the use of the common
catalyst 3a was recommended.
Having established the best protocol to extend the
reaction, we studied the possibility of using different alde-
hydes as well as different 1,3-dinucleophiles to synthesize
various pentasubstituted cyclohexane derivatives. Thus, a
broad spectrum of b-alkyl-substituted aldehydes (1a–g)[11]
could be used as the electrophile reacting with 2a, with a
general high preference for one diastereoisomer. The major
isomer was in all cases isolated in good yields and with high
enantioselectivity (Table 2, entries 1–8, in which the yields
given are for the major diastereoisomer). The substituent in
the b position of the aldehyde was found to have a strong
effect on the stereoselectivity of the process. Reactions with
more bulky alkyl substituents proceeded with better enantio-
selectivity (Table 2, entries 2–4). The scope of the reaction
could also be extended to functionalized aldehydes bearing a
protected alcohol (Table 2, entry 6) as well as an alkenyl
moiety (Table 2, entry 7). In both cases the enantioselectivity
is maintained at high levels.
MeOC6H4)
12
13
14
15
16
17
1d (iPr)
1d (iPr)
1d (iPr)
1d (iPr)
1a (Et)
1d (iPr)
2d (o-MeC6H4) 4l: 48 (71) 5:2:1 90
2e (p-MeC6H4) 4m: 40 5:1:1.2 84
2 f (p-ClC6H4) 4n: 47 5:1:1 88
2g (naphth-2-yl) 4o: 61
2h (furan-2-yl)
2h (furan-2-yl)
5:0:1 88
4:2:1 86
4p: 60
4q: 43
(52[e])
6:1:0
4:0:1 80
5:1:1 90
88
18
19
1a (Et)
2i (thiophen-2- 4r: 42
yl)
2i (thiophen-2- 4s: 43
yl)
1d (iPr)
[a] The reaction wascarried out on a 0.2-mmol scale of 1a and 2a, using
20 mol% of the catalyst 3a and DABCO (10 mol%) in a vial containing
0.25 mL of CH2Cl2. [b] Yield of the isolated major stereoisomer
(combined yield of the three stereoisomers). [c] Determined by NMR
spectroscopy of the reaction mixture. The minor diastereoisomers were
also characterized for 4a. [d] Determined by HPLC on a chiral stationary
phase. [e] Combined yield of the two stereoisomers. [f] Reaction carried
out on a 0.1-mmol scale. TIPS=triisopropylsilyl.
evaluated by treating 1d with the different dinitro compounds
2b–i. Changing the electronic properties of the aromatic
substituent in the nucleophile had no major effect on the
stereoselectivity of the reaction. Electron-withdrawing as well
as electron-donating groups could be attached to the aromatic
moiety, and gave rise to the cyclohexanols 4j–o with
comparable diastereoselectivities and enantioselectivities in
the range of 88–90% ee. Only in the case of the p-tolyl-
substituted nucleophile 2e was a slight decrease in enantio-
selectivity observed (Table 2, entry 13). Finally, furanyl- and
thiophenyl-substituted nucleophiles 2h and 2i were also
shown to be compatible in this reaction, and provided the
corresponding cyclohexanol derivatives 4p–s with yields and
diastereoselectivities within the ranges observed before, and
with enantioselectivities of up to 90% ee. Similar results were
obtained from reactions giving 4a and 4c performed on a 1-
mmol scale.
Other 1,3-dinucleophiles were compatible with this meth-
odology. As Table 2shows, aromatic and heteroaromatic
substituted nucleophiles 2b–i could be used in this reaction,
with the desired products formed with similar yields and
stereoselectivities (Table 2, entries 9–19). Again, the more
bulky isopropyl-substituted aldehyde 1d gave the best results
in terms of diastereoselectivity (Table 2, compare entries 9
and 10). Consequently, the scope of the reaction was
Angew. Chem. Int. Ed. 2007, 46, 9202 –9205
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9203
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Take advantage of blue reference links
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

Communications
The asymmetric domino organocatalytic nitro-Michael/
which indicates that the initial addition takes place from the
Re face through the control of the catalyst. From the absolute
configuration at C-1 and C-2, we assume that the final
assembly takes place from the Si face of the carbonyl group,
which suggests no catalyst involvement during this bond
formation.
Henry reaction for the synthesis of the cyclohexanol deriv-
atives 4 can be explained by an initial iminium activation of
the a,b-unsaturated aldehyde 1 by catalyst 3, followed by an
intramolecular nitro-aldol reaction as outlined in Scheme 2.
In the first step, an activation of the aldehyde as an iminium
In conclusion, we have developed the addition of nitro-
alkanes to a,b-unsaturated aldehydes followed by an intra-
molecular Henry reaction which leads to the formation of
highly substituted cyclohexanols with control over five
contiguous stereocenters. This novel domino reaction cata-
lyzed by the commercially available diarylprolinol silyl ether
3a proceeds with moderate to good yields and with high
diastereo- and enantioselectivity. The optically active cyclo-
hexanols arising from this domino process constitute valuable
chiral building blocks since they contain the b-amino alcohol
functional motif which is ubiquitous in biologically active
compounds.[13]
Experimental Section
An ordinary vial equipped with a magnetic stirring bar was charged
with catalyst 3a (0.04 mmol, 20 mol%), DABCO (0.02 mmol,
10 mol%), and CH2Cl2 (0.25 mL). Then, 2 (0.2mmol) and the a,b-
unsatured aldehyde 1 (0.2mmol) were added. The stirring was
maintained at room temperature until completion of the reaction and
the crude reaction mixture was directly charged on to silica gel and
subjected to flash chromatography.
Scheme 2. Proposed mechanism for the organocatalyzed asymmetric
nitro-Michael/Henry domino reaction.
Representative example: (1R,2S,3R,4R,5R)-5-Ethyl-2,4-dinitro-
3-phenylcyclohexanol (4a) was isolated by flash chromatography (n-
1
hexane/AcOEt gradient from 9.5:0.5 to 8:2) in 45% yield. H NMR
ion occurs, which allows the formation of the Michael adduct
by attack of the nucleophile from the less hindered face. After
hydrolysis of the iminium ion, the nitroaldehyde intermediate
undergoes a subsequent intramolecular Henry reaction which
generates the final product 4 with five contiguous stereocen-
ters.
The absolute configuration of the major stereoisomer was
assigned by single-crystal X-ray analysis of the p-chloroben-
zoate derivative of 4a (Figure 1).[12] The structure leads to a
1R,2S,3R,4R,5R assignment of the formed stereocenters,
(400 MHz, CDCl3): d = 7.53–7.08 (m, 5H), 5.93 (dd, J = 12.4, 2.5 Hz,
1H), 5.02(t, J = 4.4 Hz, 1H), 4.79 (brs, 1H), 4.17 (dd, J = 12.4 Hz,
1H), 2.58 (brs, 1H), 2.53–2.42 (m, 1H), 2.20 (td, J = 13.5, 2.0 Hz, 1H),
2.06 (td, J = 14.5, 4.2Hz, 1H), 1.45–1.20 (m, 2H), 1.01 ppm (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 134.3, 129.3, 128.6,
127.0, 92.1, 85.9, 67.5, 41.7, 34.7, 32.1, 24.6, 11.3 ppm; HRMS: calcd
for [C14H18N2O5Na]+: 317.1113; found: 317.1122. M.p. 153–1558C (n-
hexane/AcOEt). The ee value was determined by HPLC on a
Chiralpak AS column (hexane/iPrOH 95:5); flow rate 1.0 mLminÀ1
;
tmajor = 20.8 min, tminor = 24.4 min (90% ee). [a]RDT = À49.8 (c = 0.75,
CHCl3).
Received: September 27, 2007
Published online: November 5, 2007
Keywords: a,b-unsaturated aldehydes · asymmetric synthesis ·
.
domino reaction · nucleophilic addition · organocatalysis
[1] a) K. C. Nicolaou, T. Montagnon, S. A. Snyder, Chem. Commun.
2003, 551; b) K. C. Nicolaou, D. J. Edmonds, P. G. Bulger,
Angew. Chem. 2006, 118, 7292; Angew. Chem. Int. Ed. 2006,
45, 7134.
[2] For recent reviews on tandem and domino strategies for
enantioselective synthesis, see a) C. J. Chapman, C. G. Frost,
Synthesis 2007, 1, and references therein; b) L. F. Tietze, G.
Brasche, K. Gericke, Domino Reactions in Organic Synthesis,
Wiley-VCH, Weinheim, 2006; c) T. J. J. Muller, Metal Catalysed
Cascade Reactions, Wiley-VCH, Weinheim, 2006; d) J. Zhu, H.
BienaymØ, Multicomponent Reactions, Wiley-VCH, Weinheim,
2005; e) J. C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan,
Chem. Rev. 2005, 105, 1001; f) L. F. Tietze, Chem. Rev. 1996, 96,
Figure 1. X-ray structure of the p-chlorobenzoate derived from 4a.
C gray, N blue, O red, Cl green. H atomsare omitted for clarity.
9204 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 9202 –9205
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Take advantage of blue reference links
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

Angewandte
Chemie
115; g) L. F. Tietze, F. Haunert, in Stimulating Concepts in
Chemistry (Eds.: F. Vögtle, J. F. Stoddart, M. Shibasaki), Wiley-
VCH, Weinheim, 2000.
see c) N. Ono, The Nitro Groupin Organic Synthesis , Wiley-
VCH, New York, 2001; d) R. Ballini, G. Bosica, D. Fiorini, A.
Palmieri, M. Petrini, Chem. Rev. 2005, 105, 933; for examples,
see e) M. Yamaguchi, T. Shiraishi, Y. Igarashi, M. Hirama,
Tetrahedron Lett. 1994, 35, 8233; f) M. Yamaguchi, Y. Igarashi,
R. S. Reddy, T. Shiraishi, M. Hirama, Tetrahedron 1997, 53,
11223; g) S. Hanessian, V. Pham, Org. Lett. 2000, 2, 2975; h) B.
Vakulya, S. Varga, A. Csµmpai, T. Soós, Org. Lett. 2005, 7, 1967;
i) K. Funabashi, Y. Saida, M. Kanai, T. Arai, H. Sasai, M.
Shibasaki, Tetrahedron Lett. 1998, 39, 7557; j) M. S. Taylor, D. N.
Zalatan, A. M. Lerchner, E. N. Jacobsen, J. Am. Chem. Soc.
2005, 127, 1313; k) N. Halland, R. G. Hazell, K. A. Jørgensen, J.
Org. Chem. 2002, 67, 8331; l) S. Hanessian, Z. Shao, J. S. Warrier,
Org. Lett. 2006, 8, 4787; m) A. Prieto, N. Halland, K. A.
Jørgensen, Org. Lett. 2005, 7, 3897; n) C. E. T. Mitchell, S. E.
Brenner, J. García-Fortanet, S. V. Ley, Org. Biomol. Chem. 2006,
4, 2039.
[3] a) D. Enders, M. R. M. Hüttl, C. Grondal, G. Raabe, Nature
2006, 441, 861; b) D. Enders, M. R. M. Hüttl, J. Runsink, C.
Raabe, B. Wendt, Angew. Chem. 2007, 119, 471; Angew. Chem.
Int. Ed. 2007, 46, 467; c) Y. Hayashi, T. Okano, S. Aratake, D.
Hazelard, Angew. Chem. 2007, 119, 5010; Angew. Chem. Int. Ed.
2007, 46, 4922; d) H. Y. Kim, A. E. Lurain, P. Garcia-Garcia, P. J.
Carroll, P. J. Walsh, J. Am. Chem. Soc. 2005, 127, 13138; e) D. M.
Hodgson, A. H. Labande, F. Y. T. M. Pierard, Synlett 2003, 59;
f) H. A. Dondas, C. W. G. Fishwick, X. Gai, R. Grigg, C. Kilner,
N. Dumrongchai, B. Kongkathip, N. Kongkathip, C. Polysuk, V.
Sridharan, Angew. Chem. 2005, 117, 7742; Angew. Chem. Int. Ed.
2005, 44, 7570; g) C. Lim, J.-E. Kang, J.-E. Lee, S. Shin, Org. Lett.
2007, 9, 3539.
[4] A. Carlone, S. Cabrera, M. Marigo, K. A. Jørgensen, Angew.
Chem. 2007, 119, 1119; Angew. Chem. Int. Ed. 2007, 46, 1101.
[5] For recent reviews on organocatalytic cascade reactions, see for
example: a) D. Enders, C. Grondal, M. R. M. Hüttl, Angew.
Chem. 2007, 119, 1590; Angew. Chem. Int. Ed. 2007, 46, 1570;
b) G. Guillena, D. J. Ramón, M. Yus, Tetrahedron: Asymmetry
2007, 18, 693; c) M. Yus, D. J. Ramón, Angew. Chem. 2005, 117,
1628; Angew. Chem. Int. Ed. 2005, 44, 1602; d) F. LiØby-Muller,
C. Simon, T. Constantieux, J. Rodriguez, QSAR Comb. Sci. 2006,
25, 432; for a recent review on organocatalytic enantioselective
conjugate additions, see for example: e) J. L. Vicario, D. Badía,
L. Carrillo, Synthesis 2007, 2065; for examples, see f) U. Eder, G.
Sauer, R. Wiechert, Angew. Chem. 1971, 83, 492; Angew. Chem.
Int. Ed. Engl. 1971, 10, 496; g) Z. G. Hajos, D. R. Parrish, J. Org.
Chem. 1974, 39, 1615; h) G. Zhong, T. Hoffmann, R. A. Lerner,
S. Danishefsky, C. F. Barbas III, J. Am. Chem. Soc. 1997, 119,
8131; i) B. List, R. A. Lerner, C. F. Barbas III, Org. Lett. 1999, 1,
59; j) T. Bui, C. F. Barbas III, Tetrahedron Lett. 2000, 41, 6951;
k) T. Itoh, M. Yokoya, K. Miyauchi, K. Nagata, A. Ohsawa, Org.
Lett. 2003, 5, 4301; l) N. Halland, P. S. Aburel, K. A. Jørgensen,
Angew. Chem. 2004, 116, 1292; Angew. Chem. Int. Ed. 2004, 43,
1272; m) J. Pukkinen, P. S. Aburel, N. Halland, K. A. Jørgensen,
Adv. Synth. Catal. 2004, 346, 1077; n) Y. Yamamoto, N.
Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2004, 126, 5962;
o) Y. Huang, A. Walji, C. H. Larsen, D. W. C. MacMillan, J. Am.
Chem. Soc. 2005, 127, 15051; p) J. W. Yang, M. T. Hechavarria
Fonseca, B. List, J. Am. Chem. Soc. 2005, 127, 15036, and
references therein; q) E. Reyes, J. L. Vicario, D. Badia, L.
Carrillo, Org. Lett. 2006, 8, 6135; r) H. Jiang, J. B. Nielsen, M.
Nielsen, K. A. Jørgensen, Chem. Eur. J. 2007, 13, 9068.
[7] For reviews, see for example: a) G. Rosini in Comp. Org. Synth.
(Eds.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991; b) M.
Shibasaki, H. Groger, in Comprehensive Asymmetric Catalysis I–
III (Eds.: E. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999; c) F. A. Luzzio, Tetrahedron 2001, 57, 915; d) C.
Palomo, M. Oiarbide, A. Laso, Eur. J. Org. Chem. 2007, 2561;
e) J. Boruwa, N. Gogoi, P. P. Saikia, N. C. Barua, Tetrahedron:
Asymmetry 2006, 17, 3315; for examples, see f) C. Christensen,
K. Juhl, K. A. Jørgensen, Chem. Commun. 2001, 2 2 2 2 ; g) T.
Risgaard, K. V. Gothelf, K. A. Jørgensen, Org. Biomol. Chem.
2003, 1, 153; h) D.-M. Du, S-F. Lu, T. Fang, J. Xu, J. Org. Chem.
2005, 70, 3712; i) D. Uraguchi, S. Sakaki, T. Ooi, J. Am. Chem.
Soc. 2007, 129, 12392; j) T. Arai, M. Watanabe, A. Yanagisawa,
Org. Lett. 2007, 9, 3595.
[8] For the synthesis of the 1,3-dinitroderivative, see R. Ballini, G.
Bosica, D. Fiorini, A. Palmieri, Synthesis 2004, 1938.
[9] For design and mechanistic insights with this catalyst, see a) J.
Franzen, M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjars-
gaard, K. A. Jørgensen, J. Am. Chem. Soc. 2005, 127, 18296; for
the characterization and synthesis of the catalyst, see b) M.
Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen, Angew.
Chem. 2005, 117, 804; Angew. Chem. Int. Ed. 2005, 44, 795.
[10] Other base additives tested led to lower enantioselectivities. The
reaction rate is considerably lower in the absence of DABCO
and in the presence of acids.
[11] For the synthesis of aldehyde 1 f, see S. Cardani, C. De Toma, C.
Gennari, C. Scolastico, Tetrahedron 1992, 48, 5557.
[12] CCDC-662261 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[6] a) D. Enders, A. A. Narine, T. Benninghaus, Synlett 2007, 1667;
b) C. Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente, S.
Vera, Angew. Chem. 2007, DOI: 10.1002/ange.200703261;
Angew. Chem. Int. Ed. 2007, DOI: 10.1002/anie.200703261
(this paper was available on the internet during the reviewing
of this mansucript); for recent reviews with extensive references,
[13] For a review, see G. M. Coppola, H. F. Schuster, Asymmetric
Synthesis. Construction of Chiral Molecules Using Amino Acids,
Wiley-VCH, New York, 1987.
Angew. Chem. Int. Ed. 2007, 46, 9202 –9205
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 9205
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&
&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
&
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&
Take advantage of blue reference links
&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&