A rational approach towards a new ferrocenyl pyrrolidine for stereoselective enamine catalysis

Article abstract of DOI:10.1002/chem.201300959

Ironing out the details: Proline and pyrrolidine derivatives (Hayashi- J?rgensen catalysts) are considered work horses in organocatalysis. This report describes a new effective ferrocenyl pyrrolidine catalyst that is able to perform well in benchmark organocatalytic reactions (see figure). The ferrocene moiety controls the conformational space and a simple alkyl group effectively covers a face of the derived enamine. This new framework can find applications in organocatalysis, and in general, in new ligand design. Copyright

Full text of DOI:10.1002/chem.201300959

COMMUNICATION
DOI: 10.1002/chem.201300959
A Rational Approach Towards a New Ferrocenyl Pyrrolidine for
Stereoselective Enamine Catalysis
Diego Petruzziello,[a] Marco Stenta,[b] Andrea Mazzanti,[c] and Pier Giorgio Cozzi*[a]
Research in the field of organocatalysis has grown expo-
nentially in the last decade,[1] and organocatalytic modes of
activation are currently employed in the synthesis of com-
plex natural products[2] and drugs.[3] Most of the stereoselec-
tive organocatalytic reactions are based on the two basic ac-
tivation modes[4] of enamino[5] and iminum catalysis,[6] as dis-
played by selected secondary amines bearing a pyrrolidine
core.[7]
oxygen atom (catalyst II), which allows for additional struc-
tural diversification by varying the groups on the silicon
atom. In this case, the presence of the aryl groups is re-
quired for stereo direction. On the other hand, Palomo and
co-workers[10] have demonstrated the use of a pyrrolidine
bearing a long alkyl chain for reactions carried out in the
presence of water. Maruoka has shown that a 2-tritylpyrroli-
dine is also a quite effective organocatalyst,[11] and more re-
cently, Bolm, Christmann, and Strohmann, and Franz have
independently synthetized new organocatalysts based on si-
lylated pyrrolidines.[12] In most of the examples cited, the
presence of a diaryl or triaryl moiety is required to fix the
conformation of the enamine, and to effectively shield one
face from the attack of electrophiles.
The nickname “work-horses”[8] of enantioselective orga-
nocatalysis was assigned to proline, proline derivatives, or
other five-membered heterocycles (structures I–V, Figure 1)
due to their extensive use in this field. In particular the
most commonly used diaryl-pyrrolidine derivatives, the Hay-
ashi and Jørgensen organocatalysts,[9] are silylated at the
The “geminal-diaryl effect” (stereodirection through con-
formational fixation) is a well-known result of bulky sub-
stituents and it has been exploited throughout the field of
stereoselective organic synthesis.[13] Not only are two aryl
groups, like phenyl, capable of fixing the conformation
around a neighboring single bond, but they also become
powerful stereodirectors in chiral molecules, in which the
two aryl groups become diastereotopic, as in BINAP (2,2’-
bis(diphenylphosphino)-1,1’-binaphthyl)[14] or in TADDOL
(a,a,a,a-tetraaryl-1,3-dioxolane-4,5-dimethanols).[15] Even in
the modified Evans auxiliary DIOZ (3-(1-methylethyl)-5,5-
diphenyloxazolidin-2-one) the diastereotopic aryl groups im-
prove functional-group stereoselectivity.[16]
In this communication, we present the synthesis of new,
effective ferrocenyl pyrrolidine catalysts bearing alkyl
chains. In this catalyst the preferred conformation of the
pyrrolidine ring is imposed by the interaction between a fer-
rocene moiety and the two alkyl groups. In addition, we
proved that the enamine formed by these new organocata-
lysts is effective in benchmark organocatalytic reactions.
Ferrocene can be considered a “privileged framework”
for the construction of effective chiral ligands.[17] Surprising-
ly, pyrrolidine bearing a ferrocene moiety has not been con-
sidered as a viable tool to control catalysts conformation in
enamine/iminium catalysis.[18] However, with the introduc-
tion of metal fragments in the molecule, the catalysts descri-
bed here cannot be considered, strictly speaking, an organo-
catalyst. Nevertheless it should be noted that the ferrocene
moiety can act exclusively as a bulky group, in which the
iron center is not involved in the reaction and does not pro-
vide attractive charge-dipole effects. These phenomena, par-
Figure 1. The catalysts extensively used as “work horses” in organocataly-
sis.
[a] Dr. D. Petruzziello, Prof. P. G. Cozzi
ALMA MATER STUDIORUM
Dipartimento di Chimica “G. Ciamician”
Via Selmi 2, 40126 Bologna (Italy)
Fax : (+39)051-2099456
E-mail: piergiorgio.cozzi@unibo.ir
[b] Dr. M. Stenta
Institute of Bioengineering, School of Life Science
Ecole Polythechnique Fꢀdꢀrale de Lausanne
EPFL, Lausanne, 1015 (Switzerland)
[c] Prof. A. Mazzanti
ALMA MATER STUDIORUM, Dipartimento di Chimica Industri-
ale “Toso Montanari” Viale Risorgimento 40136, Bologna (Italy)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300959.
À
ticularly in C F bonds were recently used by Gilmour for
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

an effective pre-organisation strategies for enantio- and dia-
steroselective reaction design in iminum catalysis.[19]
tional equilibrium. Quite remarkably we noticed that the
energy spread of conformers is significantly reduced by aryl
groups, while much smaller and simpler alkyl chains were
able to favor only one conformer (M3-S, see the Supporting
Information) over the possible ones. In particular ethyl moi-
eties showed the best compromise between effectiveness
and size (Figure 3).
To start designing some possible structures, we considered
the frame of the Hayashi–Jørgensen catalyst, and replaced
the OSiMe3 group with a ferrocenyl group. In order to avoid
the preparation of many derivatives, and the attempts to
separate the enantiomers by chemical resolution, we started
with a careful theoretical investigation, on this initial de-
signed catalyst. This molecule possess two major conforma-
tional degrees of freedom (CDF) associated to the dihedral
angles w, defined as C5-(C1-C6)-C7, and f, defined as C1-
(C6-C7)-N8 (Figure 2). To discover the conformation equili-
Figure 3. Preferred conformations of the enamine 5, calculated at the
RIJCOSX-B3LYP/def2-TZVPP level. Energies in kcalmolÀ1 (relative to
the lowest energy structure).
Figure 2. Geometrical parameters defining the conformational space of
the ferrocenyl pyrrolidine catalyst.
À
The rotational equilibrium around the C6 C7 bond was
investigated for both methyl- (M4-S, Supporting Informa-
tion) and ethyl- (M5-S, Supporting Information) substituted
enamine adducts. In the presence of methyl substituents the
energy spread between rotamers is as small as in the pyrroli-
dine-substituted system (M2-S). The presence of an ethyl
group strongly reduces the conformational freedom around
this bond, as only one rotamer was predicted to be populat-
ed. In this rotamer, one of the ethyl groups is hindering the
bottom face of the enamine 5.
Based on the theoretical analysis, we selected the diethyl
ferrocenyl pyrrolidine 3 as a candidate for the synthetic
evaluation. The synthesis of the enantiomerically pure 3 was
devised as reported in Scheme 1.
brium of the investigated catalyst, we employed accurate
quantum mechanical calculations (RIJCOSX-B3LYP/def2-
TZVPP optimization). Since the full exploration of the con-
formational space of the enamine adduct would have re-
quired an overwhelming effort, a different strategy was put
in place. The enamine was constructed stepwise by adding
molecular fragments to an initial ferrocene; at each step the
relevant degrees of freedom were explored and the lowest
conformer underwent the following step. Besides a noticea-
ble saving in computing time, this approach provided useful
insights on the effects of each molecular fragment to the
overall conformational equilibrium. Both metal–carbon
(2.09 ꢂ) and cyclopentadienyl carbon–carbon distances, ob-
tained by optimization of eclipsed and staggered conforma-
tions of the unsubstituted ferrocene (model Fe 1 and Fe 2
in the Supporting Information), were in close agreement
with those reported previously.[20] The optimized staggered
The ferrocenyl ethyl ketone 6[21] was transformed in a
straightforward manner in the tertiary alcohol. The resulting
product was then treated with pyrrole in the presence of a
catalytic amount of InBr3 (10 mol%) to give 7 in high
yield.[22] No traces of the b-pyrrole isomer was detected.
Due to the reactivity of pyrrole, the reaction was conducted
using an excess of this reagent at low temperature. The com-
pound 7, after chromatographic purification, was hydrogen-
ated with 1 atmosphere of hydrogen by using a rhodium on
graphite[23] catalyst to give the racemic pyrrolidine 3 in high
yield. The racemic mixture was then separated by the syn-
thesis of the corresponding O-acetyl-mandelic amide 8.[24]
The chromatographic separation by preparative TLC was
quite straightforward. The hydrolysis of the isolated diaster-
oisomers of 8 proved to be quite difficult. In standard reac-
tion conditions and in the presence of excess of KOH or
NaOH no reaction was observed. However, by the treat-
ment of the amide with an excess of tBuOK in THF under
refluxing conditions[25] for 36 h, we were able to cleave the
amide bond. The desired enantioenriched 2-(diethylferroce-
nyl)pyrrolidine 3 was isolate in satisfactory yields.
À
À
conformation (Fe C=2.081 ꢂ, C C=1.422 ꢂ) was used to
build a tert-butyl derivative (model M1, see the Supporting
Information) in order to study the energy difference be-
tween two possible rotamers M1 1 and 2 (Supporting Infor-
mation). Geometry optimizations revealed M1 1 to be a
stable minimum on the potential energy surface (PES); no
other stable conformers were individuated. The substitution
of a methyl with the pyrrolidine ring increases the number
of possible conformers. Three stable rotamers were identi-
fied by relaxed scan along the f dihedral angle, with the
three minima lying in an energy range as narrow as 1.44 kcal
molÀ1. Alkyl and aryl groups were then introduced to assess
the influence exerted on this conformational equilibrium by
C6-substituents of different size and shape. We expected to
find a direct and linear correlation between the size of the
substituents and their capability in controlling the conforma-
&
2
&
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

A Ferrocenyl Pyrrolidine for Stereoselective Enamine Catalysis
COMMUNICATION
of the mandelate was almost identical to the structure of the
lowest energy conformer (Figure 4). The enamine 5 can be
obtained in situ (in [D6]DMSO) by the direct reaction of
propanal with the catalyst 3.[26] A careful 1D NOESY study,
performed on the stable enamine, confirmed both the E ge-
ometry of the enamine, and the conformation of the enam-
ine calculated by DFT, thus ratifying the reliability of the
theoretical studies. (See the Supporting Information for de-
tails). Next, (S)-2-(diethylferrocenyl)pyrrolidine 3 (96–99%
ee as proven by its HPLC analysis after derivatization to the
corresponding 3,5-dinitrophenylamide; see the Supporting
Information for details and for HPLC traces), was applied
in catalytic asymmetric nitro-Michael addition reactions of
aldehydes 9a and c to nitro alkene 10a and c (Table 1).
Table 1. Organocatalytic addition of aldehydes to nitroalkenes promoted
by 3.[a]
Scheme 1. Synthesis of racemic and enantioenriched ferrocenylpyrroli-
dine.
Product
t [h]
Yield [%][b]
d.r.[c]
ee[%][d]
syn
1
11aa
11aa
11ba
11ca
11ab
11ac
14
14
16
60
20
40
73
75
70
74
98
98
8:1
8:1
10:1
24:1
30:1
12:1
88
95
88
89
87
91
2[e]
3
4
5
6
[a] The reactions were performed at 08C with 1 equivalent of nitroalkene
10, 10 equivalents of aldehyde 9, in the presence of 10 mol% of catalyst
(S)-3 (96% ee) and the reactions were run until completion checked by
TLC (16–60 h). [b] Yield after chromatographic purification. [c] For all
1
the reactions the d.r. (syn vs. anti) was measured by H NMR and HPLC
analysis. [d] Determined by chiral HPLC analysis. See Supporting Infor-
mation for details. [e] (S)-3 of 99% ee was used for the reaction.
Solvent screening experiments showed that hexane was
the optimal solvent as it gives the best results in terms of
stereoselectivity and yield. To our delight the excellent re-
sults, obtained under selected reaction conditions (see
Table 1), confirmed our hypothesis about the ability of the
catalyst in discriminating one face of the enamine.
It should be noted that, in contrast to the Hayashi–Jør-
gensen catalyst, the ferrocenyl compound 3 is a remarkably
robust and recoverable catalyst and is not easily decom-
posed by acids or bases. In order to prove that the catalyst
was of general use, we tested the performance of 3 in orga-
nocatalytic SN1-type alkylations[27] of enamines with the
bis[4-(dimethylamino)phenyl] methanol 12 and the propar-
gylic alcohol 14 (Scheme 2). Pleasantly, we found the cata-
lyst gave satisfactory results in line with the recently devel-
oped silyl modified analogues of 2-tritylpyrrolidine,[12b]
showing that the catalyst 3 was also able to promote differ-
ent organocatalytic reactions. It worth mentioning that the
Figure 4. Determination of the configuration of the slow eluted amide
obtained by reaction of 3 with (S)-OAc-mandelic chloride.
The absolute (S,S) configuration of the more retained dia-
stereoisomer was established by X-ray analysis (see the Sup-
porting Information for further details). The X-ray structure
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

P. G. Cozzi et al.
hexane/isopropanol
95:5;
flux=
1.0 mLminÀ1
;
T=308C. The crude
product was then purified by flash
chromatography on silica (cyclohex-
ane/ethyl acetate) gives the pure prod-
ucts in 90 to 99% yield.
Acknowledgements
PRIN (Progetto Nazionale Stereosele-
zioni in Chimica Organica: Metodolo-
gie ed Applicazioni), Bologna Univer-
sity, Fondazione Del Monte and the
European Commission through the
project FP7–201431(CATAFLU.OR)
are acknowledged for financial sup-
port
Keywords: enamines
·
Scheme 2. SN1-type reaction of the alcohols 12 and 14 with the aldehydes 9a and b promoted by 10 mol% of
the catalyst 3.
ferrocene
reaction
·
nitro-Michael
·
organocatalysis
·
pyrrolidine
Hayashi–Jørgensen catalyst is not compatible with the pres-
ence of InIII salts in the reaction mixture.[28]
We have performed DFT calculations in order to clarify
[1] For reviews, see: a) P. Melchiorre, M. Marigo, A. Carlone, G. Barto-
li, Angew. Chem. 2008, 120, 6232–6265; Angew. Chem. Int. Ed.
2008, 47, 6138–6171; b) C. F. Barbas III, Angew. Chem. 2008, 120,
44–50; Angew. Chem. Int. Ed. 2008, 47, 42–47; c) G. Lelais,
D. W. C. MacMillan, Aldrichimica Acta 2006, 39, 79–87.
[2] a) S. B. Jones, B. Simmons, D. W. C. MacMillan, J. Am. Chem. Soc.
2009, 131, 13606–13607; b) J. Carpenter, A. B. Northrup, D. M.
Chung, J. J. M. Wieners, S.-G. Kim, D. W. C. MacMillan, Angew.
Chem. 2008, 120, 3624–3628; Angew. Chem. Int. Ed. 2008, 47, 3568–
3572.
[3] J. E. Wilson, A. D. Casarez, D. W. C. MacMillan, J. Am. Chem. Soc.
2009, 131, 11332–11333.
[4] D. W. C. MacMillan, Nature 2008, 455, 304–308.
[5] A. Errkilꢄ, I. Majander, P. M. Pihko, Chem. Rev. 2007, 107, 5416–
5470.
the selectivity of the nitro Michael reaction (See the Sup-
porting Information for full details).[29] The conformational
constraints imposed by ferrocene also drive the conforma-
tion of the ethyl groups, thus resulting in the effective
screening of one face of the enamine intermediate. The less
hindered enamine face reacts with the nitro derivative
giving a zwiterrionic intermediate.
In conclusion, we have developed a new 2-(diethylferro-
cenyl) pyrrolidine catalyst, active in benchmark organocata-
lytic reactions. The ferrocenyl moiety, in combination with
simple ethyl chains, is capable of fixing the enamine confor-
mation addressing the approach trajectory of the nucleo-
phile reaction partner. The results presented here represent
an interesting proof-of-concept, showing for the first time
the remarkable effectiveness of the ferrocenyl moiety in
providing enantioselectivity through conformational selec-
tion.[30] This approach could be viably employed in the ra-
tional design of ligands for organometallic or organocatalyt-
ic reactions.
[6] S. Mukherjee, J. W. Yang, S. Hoffmann, B. List, Chem. Rev. 2007,
107, 5471–5569.
[7] H. Mayr, S. Lakhdar, B. Maji, A. R. Ofial, Beilstein J. Org. Chem.
2012, 8, 1458–1478.
˘
[8] D. Seebach, U. Groselj, D. M. Badine, W. B. Schweizer, A. K. Beck,
Helv. Chim. Acta 2008, 91, 1999–2034.
[9] For the first reports on Jørgensen–Hayashi catalysts, see: a) M.
Marigo, T. C. Wabnitz, D. Fielenbach, K. A. Jørgensen, Angew.
Chem. 2005, 117, 804–807; Angew. Chem. Int. Ed. 2005, 44, 794–
797; b) Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji, Angew. Chem.
2005, 117, 4284–4287; Angew. Chem. Int. Ed. 2005, 44, 4212–4215.
For reviews see: C. Palomo, A. Mielgo, Angew. Chem. 2006, 118,
8042–8046; Angew. Chem. Int. Ed. 2006, 45, 7876–7880;K. L.
Jensen, G. Dickmeiss, H. Jiang, Ł. Albrecht, K. A. Jørgensen, Acc.
Chem. Res. 2012, 45, 248–264.
[10] C. Palomo, A. Landa, A. Mielgo, M. Oiarbide, A. Puente, S. Vera,
Angew. Chem. 2007, 119, 8583–8587; Angew. Chem. Int. Ed. 2007,
46, 8431–8435.
[11] T. Kano, H. Mii, K. Maruoka, J. Am. Chem. Soc. 2009, 131, 3450–
3451.
Experimental Section
General procedure for the synthesis of compounds 12: In a vial the enan-
tioenriched catalyst (S)-3 (3.3 mg, 0.01 mmol, 0.05 equiv.) was dissolved
in hexane, then the nitro alkene (0.2 mmol, 1 equiv.) and benzoic acid
(1.2 mg, 0.01 mmol, 0.05 equiv.) were added. The mixture was cooled to
08C and then the aldehyde (2 mmol, 10 equiv.) was added at 08C. The re-
action mixture was stirred at 0C8 temperature for 10–24 h. The reaction
was quenched at 08C by the addition of HCl (1 mL, 1n), then the mix-
ture was extracted with diethyl ether (2ꢃ3 mL). The organic phases were
collected, dried over Na2SO4 and evaporated under reduced pressure.
The crude product was analyzed with chiral HPLC: IA column; n-
[12] a) R. Husmann, M. JÅrres, G. Raabe, C. Bolm, Chem. Eur. J. 2010,
16, 12549–12558; b) J. O. Bauer, J. Stiller, E. Marquꢀz Lꢅpez, K.
Strohfeldt, M. Christman, C. Strohmann, Chem. Eur. J. 2010, 16,
&
4
&
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

A Ferrocenyl Pyrrolidine for Stereoselective Enamine Catalysis
COMMUNICATION
12553–12558; c) K. I. Jentzsch, T. Min, J. I. Etcheson, J. C. Fettinger,
A. K. Franz, J. Org. Chem. 2011, 76, 7065–7075.
[13] a) R. Noyori, Angew. Chem. 2002, 114, 2108–2123; Angew. Chem.
Int. Ed. 2002, 41, 2008–2022; b) B. M. Trost, J. Org. Chem. 2004, 69,
5813–5837.
[25] For a discussion about hydrolysis of amides, see: J. Aubꢀ, Angew.
Chem. 2012, 124, 3117–3119; Angew Chem. Int. Ed, 2012, 51, 3063–
3065, and references therein.
[26] a) M. B. Schmid, K. Zeitler, R. M. Gschwind, J. Am. Chem. Soc.
2011, 133, 7065–7074; b) M. B. Schmid, K. Zeitler, R. M. Gschwind,
Chem. Sci. 2011, 2, 1793–1803.
[27] For a highlight, see: P. G. Cozzi, F. Benfatti, Angew. Chem. 2010,
122, 264–267; Angew. Chem. Int. Ed. 2010, 49, 256–259. See:
a) P. G. Cozzi, F. Benfatti, L. Zoli, Angew. Chem. 2009, 121, 1339–
1342; Angew. Chem. Int. Ed. 2009, 48, 1313–1316; b) M. Guiteras
Capdevila, F. Benfatti, L. Zoli, M. Stenta, P. G. Cozzi, Chem. Eur. J.
2010, 16, 11237–11241; c) A. Gualandi, E. Emer, M. Guiteras Cap-
devila, P. G. Cozzi, Angew. Chem. 2011, 123, 7988–7992; Angew.
Chem. Int. Ed. 2011, 50, 7842–7846.
[14] a) D. Seebach, A. K. Beck, M. Schiess, L. Widler, A. Wonnacott,
Pure Appl. Chem. 1983, 55, 1807–1822; b) D. Seebach, A. K. Beck,
R. Imwinkelried, S. Roggo, A. Wonnacott, Helv. Chim. Acta 1987,
70, 954–974; c) H. Pellissier, Tetrahedron 2008, 64, 10279–10317.
[15] T. Hintermann, D. Seebach, Helv. Chim. Acta 1998, 81, 2093–2126;
C. Gaul, B. W. Schweizer, P. Seiler, D. Seebach, Helv. Chim. Acta
2002, 85, 1546–1566.
[16] R. Gꢅmez Arrayꢆs, J. Adrio, J. C. Carretero, Angew. Chem. 2006,
118, 7836–7878; Angew. Chem. Int. Ed. 2006, 45, 7674–7715.
[17] For a leading and important discussion about the “geminal-diaryl”
effect for conformational fixation and stereodirection in these struc-
tures, see: M. Braun, Angew. Chem. 2012, 124, 2600–2612; Angew.
Chem. Int. Ed. 2012, 51, 2550–2562; for the diaryl effect and its im-
[28] a) K. Motoyama, M. Ikeda, Y. Miyake, Y. Nishibayashi, Eur. J. Org.
Chem. 2011, 2239–2246; b) R. Sinisi, M. V. Vita, E. A. Gualandi, E.
Emer, P. G. Cozzi, Chem. Eur. J. 2011, 17, 7404–7408.
[29] a) K. Patora-Komisarska, M. Benohoud, H. Ishikawa, D. Seebach,
Y. Hayashi, Helv. Chim. Acta 2011, 94, 719–745; b) J. Burꢇs, A.
Armstrong, D. G. Blackmond, J. Am. Chem. Soc. 2011, 133, 8822–
8823; c) G. Talavera, E. Reyes, J. L. Vicario, L. Carrillo, Angew.
Chem. 2012, 124, 4180–4183; Angew. Chem. Int. Ed. 2012, 51, 4104–
4107; d) J. Duschmalꢀ, J. Wiest, M. Wiesne, H. Wennemers, Chem.
Science 2013, 4, 1312–1318; e) G. Sahoo, H. Rahaman, A. Madarꢆsz,
I. Pꢆpai, M. Melarto, A. Valkonen, P. M. Pihko, Angew. Chem. 2012,
124, 13321–13325; Angew. Chem. Int. Ed. 2012, 51, 13144–13148;
for a highlight, see: C. Moberg, Angew. Chem. 2013, 125, 2214–
2216; Angew. Chem. Int. Ed. 2013, 52, 2160–2162.
[30] Recently, constrained pyrrolidine catalysts, in which the rigidity of
the bicyclic structure imposes a synclinal endo disposition of the
bulky substituents with respect to the pyrrolidine ring, were descri-
bed, see: M. Lombardo, A. Quintavalla, E. Montroni, C. Trombini,
Adv. Synth. Catal. 2012, 354, 3428–3443.
˘
portance in organocatalysis, see: U. Groselj, D. Seebach, D. M.
Badine, W. B. Schweizer, A. K. Beck, I. Krossing, P. Klose, Y. Haya-
shi, T. Uchimaru, Helv. Chim. Acta 2009, 92, 1225–1259.
[18] For effective and powerful “organocatalysts” bearing a ferrocene
moiety, see: G. Fu, Acc. Chem. Res. 2004, 37, 542–547.
[19] a) E.-M. Tanzer, L. E. Zimmer, W. B. Schweizer, R. Gilmour, Chem.
Eur. J. 2012, 18, 11334–11342; b) L. E. Zimmer, C. Sparr, R. Gil-
mour, Angew. Chem. 2011, 123, 12062–12074; Angew. Chem. Int.
Ed. 2011, 50, 11860–11871.
[20] S. Coriani, A. Halaand, T. Helgaker, P. Jørgensen, ChemPhysChem
2006, 7, 245–249.
[21] S. Top, B. Dauer, J. Vaissermann, G. Jaouen, J. Organomet. Chem.
1997, 541, 355–361.
[22] P. Vicennati, P. G. Cozzi, Eur. J. Org. Chem. 2007, 2248–2253.
[23] G. Falini, A. Gualandi, D. Savoia, Synthesis 2009, 2440–2446.
[24] M. Bandini, M. Gazzano, P. G. Cozzi, A. Umani-Ronchi, Eur. J.
Org. Chem. 2001, 1937–1942.
Received: March 13, 2013
Published online: && &&, 0000
Chem. Eur. J. 2013, 00, 0 – 0
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

P. G. Cozzi et al.
Ironing out the details: Proline and
Organocatalysis
pyrrolidine derivatives (Hayashi–Jør-
gensen catalysts) are considered “work
horses” in organocatalysis. This report
describes a new effective ferrocenyl
pyrrolidine catalyst able to perform
well in benchmark organocatalytic
reactions (see figure). The ferrocene
moiety controls the conformational
space and a simple alkyl group effec-
tively covers a face of the derived
enamine. This new framework can find
applications in organocatalysis, and in
general, in new ligand design.
D. Petruzziello, M. Stenta,
A. Mazzanti, P. G. Cozzi* . . &&&& — &&&&
A Rational Approach Towards a New
Ferrocenyl Pyrrolidine for Stereoselec-
tive Enamine Catalysis
&
6
&
www.chemeurj.org
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!