Isolation and X-ray structures of reactive intermediates of organocatalysis with diphenylprolinol ethers and with imidazolidinones a survey and comparison with computed structures and with 1-acyl-imidazolidinones: The 1,5-repulsion and the geminal-diaryl

Article abstract of DOI:10.1002/hlca.200890216

Reaction of 2-phenylacetaldehyde with the Me₃Si ether of diphenyl-prolinol, with removal of H₂O, gives a crystalline enamine (1). The HBF₄ salts of the MePh₂Si ether of diphenyl-prolinol and of 2-(tert-butyl)-3-

Full text of DOI:10.1002/hlca.200890216

Helvetica Chimica Acta – Vol. 91 (2008)
1999
Isolation and X-Ray Structures of Reactive Intermediates of Organocatalysis
with Diphenylprolinol Ethers and with Imidazolidinones
A Survey and Comparison with Computed Structures and with 1-Acyl-
imidazolidinones: The 1,5-Repulsion and the Geminal-Diaryl Effect at Work
1
2
by Dieter Seebach*, Uro sˇ Gro sˇ elj ), D. Michael Badine ), W. Bernd Schweizer, and Albert K. Beck
Laboratorium fꢀr Organische Chemie, Departement fꢀr Chemie und Angewandte Biowissenschaften,
ETH-Zꢀrich, Hçnggerberg, Wolfgang-Pauli-Strasse 10, CH-8093 Zꢀrich (phone: þ 41-44-632-2990;
fax: þ 41-44-632-1144; e-mail: seebach@org.chem.ethz.ch)
3
In memoriam A. I. Meyers ), who paved the way for the use of heterocycles in stereoselective organic
4
synthesis )
Reaction of 2-phenylacetaldehyde with the Me Si ether of diphenyl-prolinol, with removal of H O,
3
2
gives a crystalline enamine (1). The HBF salts of the MePh Si ether of diphenyl-prolinol and of 2-(tert-
4
2
butyl)-3-methyl- and 5-benzyl-2,2,3-trimethyl-1,3-imidazolidin-4-one react with cinnamaldehyde to give
crystalline iminium salts 2, 3, and 4. Single crystals of the enamine and of two iminium salts, 2 and 3, were
subjected to X-ray structure analysis (Figs. 1, 2, and 6), and a 2D-NMR spectrum of the third iminium salt
was recorded (Fig. 7). The crystal and NMR structures confirm the commonly accepted, general
structures of the two types of reactive intermediates in organocatalysis with the five-membered
heterocycles, i.e., D, E (Scheme 2). Fine details of the crystal structures are discussed in view of the
observed stereoselectivities of the corresponding reactions with electrophiles and nucleophiles. The
structures 1 and 2 are compared with those of other diphenyl-prolinol derivatives (from the Cambridge
File CSD; Table 1) and discussed in connection with other reagents and ligands, containing geminal diaryl
groups and being used in enantioselective synthesis (Fig. 4). The iminium ions 3 and 4 are compared with
N-acylated imidazolidinones F and G (Figs. 9, 12, and 13, and Table 3), and common structural aspects
1,3
such as minimalization of 1,5-repulsion (the ꢁA -effectꢂ), are discussed. The crystal structures of the
simple diphenyl-prolinol · HBF salt (Fig. 3) and of Boc- and benzoyl-(tert-butyl)methyl-imidazolidinone
4
(
Boc-BMI and Bz-BMI, resp.; Figs. 10 and 11) are also reported. Finally, the crystal structures are
compared with previously published theoretical structures, which were obtained from high-level-of-
theory DFT calculations (Figs. 5 and 8, and Table 2). Delicate details including pyramidalization of
trigonal N-atoms, distortions around iminium C¼N bonds, shielding of diastereotopic faces, and the p-
interaction between a benzene ring and a Me group match so well with, and were actually predicting the
experimental results that the question may seem appropriate, whether one will soon start considering to
carry out such calculations before going to the laboratory for experimental optimizations.
1)
2)
On leave from Faculty of Chemistry and Chemical Technology, University of Ljubljana, A sˇ ker cˇ eva
, PO Box 537, 1000 Ljubljana, Slovenia; financed by Slovene Human Resources Development and
Scholarship Fund, Vilharjeva 27, 1000 Ljubljana, Slovenia.
Postdoctoral Research Fellow at ETH-Zꢀrich (2006/2007), financed by grants from Novartis
Pharma AG, Basel. Present address: BASF D-Ludwigshafen.
...a great chemist, and dear friend and colleague of D. S. for over 40 years.
See his monograph ꢁ Heterocycles in Organic Synthesisꢂ, John Wiley & Sons, New York, 1974.
5
3
)
4
)
ꢃ 2008 Verlag Helvetica Chimica Acta AG, Zꢀrich

2
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Helvetica Chimica Acta – Vol. 91 (2008)
1. Introduction. – The five-membered heterocycles of type A, B, and C may be
called the work-horses of enantioselective organocatalysis. They are used for
enantioselective catalysis of the classical reactions of organic chemistry [1]: aldol
addition, aminoalkylation (Mannich, Pictet – Spengler reactions), arylation, alkylation
(
intramolecular), amination, oxidation, halogenation, thiolation of a-carbonyl posi-
tions, Michael additions to a,b-unsaturated carbonyl compounds and nitro-olefins,
nitroaldol addition (Henry reaction), hydride transfer from dihydropyridine (Hantzsch
ester), radical coupling of aldehydes with TEMPO and with electron-rich double-bond
systems, cyclopropanations, epoxidations, aziridinations, and [3 þ 2] and [4 þ 2]cy-
5
6 7
cloadditions (Diels – Alder reactions) ) ) ).
The combination of some of these reactions in so-called tandem, multiple-cascade,
domino, or multi-component transformations has led to spectacular applications, with
stereoselective formation of up to eight stereogenic centers [1l][1v]. Thus, the dream of
a synthetic organic chemist has come true: ꢁThe primary center of attention for all
synthetic methods will continue to shift toward catalytic and enantioselective variants;
indeed, it will not be long before such modifications will be available with every standard
8
9
reaction for converting achiral educts into chiral products.ꢂ ) )
6
Like all successful types of catalyst, the catalysts of the general structures A ), B,
and C can, and frequently have to, be optimized for a particular application by
combinatorial methods, and they are accessible in both enantiomeric forms, as outlined
10
for the diaryl-prolinols ) and imidazolidinones in Scheme 1.
The most commonly used diaryl-prolinol derivatives B are silylated at the O-atom
(
R ¼ OSiR ), which allows for additional structural diversification by employing
3
various R groups at Si.
2
. Structures of Reactive Intermediates in Organocatalysis by A – C. – The reactive
intermediates in the transformations catalyzed by the heterocyclic sec-amino com-
pounds A – C are chiral enamines D and iminium salts E (Scheme 2). For prolin (A)
catalysis, we have identified and/or isolated and characterized the corresponding non-
5)
6)
7)
In this expanding field of organic chemistry, we have to refer to selected reviews and a few seminal
original articles [1], and the enumeration of reactions given here cannot be complete.
Besides proline itself, derivatives such as a-methyl-proline, proline amides, a tetrazole [1r],
sulfonylimides, and (aminomethyl)-pyrrolidines [1m] have been used as catalysts.
See also the use of chiral H-bond donors [1j], of Brønsted acids [1t], and of heterocyclic carbenes
[
1p] as catalysts.
8
)
See summary of a 1990 review article entitled ꢁOrganic Synthesis – Where now?ꢂ [2].
9
)
Cf. the title ꢁIn the Golden Age of Organocatalysisꢂ [1c]; ꢁAsymmetric Organocatalysis: From
Infancy to Adolescenceꢂ [1u]; ꢁAsymmetric Aminocatalysis – Gold Rush in Organic Chemistryꢂ [1x].
The parent compound B, Arl ¼ Ph, R ¼ OH, was originally studied by physiological chemists
because of its stimulating activity [3] (effective dose 10 – 20 mg/kg, toxicity LD ¼ 150 mg/kg [3c]).
10)
50

Helvetica Chimica Acta – Vol. 91 (2008)
2001
Scheme 1. Combinatorial Preparation of Heterocycles of Type B and C. The aryl groups of diaryl-
’
prolinol, from which catalysts B (R ¼ OH, OSiR , H) are obtained, originate from aryl Grignard
3
reagents [3][4] or from benzophenones [5][6]. The imidazolidinones of type C are prepared from amino
acids, MeNH , and aldehydes or ketones [7 – 10]. Thus, an almost indefinite number of substitution
2
patterns of both types of compounds is available for optimizing a catalyst for a particular reaction (a
search for commercial aryl chlorides, bromides, and iodides, possible precursors of Grignard reagents,
furnished more than 100,000 examples, and for benzophenones more than 15,000 ꢁhitsꢂ were obtained
from the SciFinder Scholar (version 2007) data base; the number and combinations of commercial amino
acids, and aldehydes or ketones is myriad, as well, and, of course, primary amines, other than MeNH ,
2
t
can be employed (cf. the contact of an MeN group with a Me group of Bu in Fig. 10 below).
conjugated iminium ion (zwitterion) and the enamine, derived from cyclohexanone
[
11a]. Structures of enamines and iminium salts of type D and E, respectively, were not
11
found in the Cambridge Crystallographic Data File (CCDF) ) as of June 2008. On the
other hand, there are many theoretical calculations of the structures of intermediates D
and E, derived from diphenyl-prolinol [12] and imidazolidinone [1q][13][14], using
12
various levels of computation ranging from molecular modeling (MM3) ) to density
11)
For a complete list of X-ray structures of enamines with references to the CCDF and to the original
literature see [11a]. For new software for searching the Cambridge Structural Database (CSD) and
visualising crystal structures, see [11d].
In more than a dozen articles published by MacMillan and co-workers [1f][1q][13], there are mostly
superimposable MM3 models shown to rationalize the observed stereochemical courses of reactions
catalyzed by imidazolidinones of type C.
12)

2
002
Helvetica Chimica Acta – Vol. 91 (2008)
functional theory (DFT B3LYP/6-31G(d,p)), and including transition-state structures,
with or without solvent. It is tempting to ask why so much effort is being put into
computational rather than into experimental work to elucidate mechanistic aspects of
organocatalysis. One answer could be that it is so much more rewarding to find new
applications of enantioselective catalysis in a short period of time than to use oneꢂs
energy for cumbersome, excruciating, often slow-moving mechanistic work, i.e. the
13
14
field is in its exploratory discovery phase ) before it can become ꢁcontemplatingꢂ ).
Another answer may be that the computer technology and thus the theoretical
calculations have become so powerful that experimental results can be reproduced with
amazing degrees of accuracy, so that experimental mechanistic investigations may seem
to become obsolete; the problem for the simple-minded synthetic practitioner is that a
DFT calculation may result in an exact value for an activation energy but will often not
provide a qualitative mechanistic model for extrapolations in every-day laboratory
work.
Scheme 2. Reactive Intermediates D and E Formed from the Pyrrolidine and Imidazolidinone Catalysts
2
A – C, and Carbonyl Compounds. The enamine D reacts with electrophiles (d -reactivity [18]) and the
3
enoyl-iminium ion E with nucleophiles (a -reactivity). The conjugate, Michael-type addition to E
produces an enamine of type D, which, in turn, can couple intra- or intermolecularly with an electrophilic
4
5
center. Vinylogous cases, in which a dienamine exerts d -reactivity, or a dienoyl-iminium ion a -reactivity,
are also known [1].
To actually ꢁseeꢂ reactive intermediates of organocatalysis with diaryl-prolinol and
imidazolidinone derivatives, we looked for crystalline enamines D and iminium salts E.
While various simple aliphatic aldehydes and enals have so far led only to oily or
13)
In fact, organocatalysis is as old as organic chemistry [15]; for historic-background discussions, see
an essay by Barbas and co-workers [1b], and Section 11.2 in a book chapter by MacMillan and
Lelais [1f], and [11a]. The ongoing explosive development started in the year 2000 [1a].
There are several publications, in which the NMR spectra of in-situ generated intermediates are
disclosed, mainly as part of supplementary materials; see, e.g., Blackmondꢂs work discussed in
Section 4 of [11a] and the following works [1a] (PNAS) [12b][16][17]. See also Footnote 36.
14)

Helvetica Chimica Acta – Vol. 91 (2008)
2003
otherwise non-crystalline samples, 2-phenylacetaldehyde and cinnamaldehyde gave
crystalline derivatives such as the enamine 1 and the tetrafluoroborate salts 2 – 4.
We used classical methods to prepare these compounds. Thus, the enamine from
silyl ether B (R ¼ Me SiO) and 2-phenylacetaldehyde was obtained by condensation
3
with removal of the H O formed in a Dean – Stark trap. The iminium salts were
2
prepared according to a modified procedure first described by Leonard and Paukstelis,
according to which aldehydes/enals or ketones/enones and BF salts of secondary
4
amines are simply mixed in an appropriate solvent [19]. The enamine 1 and two of the
iminium salts, the pyrrolidin and the imidazolidin derivatives, 2 and 3, respectively,
could be recrystallized to give single crystals of sufficient quality for X-ray crystal-
structure analysis. The iminium salt 4 derived from the tetrasubstituted imidazolidi-
none was fully characterized spectroscopically, but could not be crystallized for a single-
crystal X-ray structure analysis.
2
.1. Enamine 1 (Fig. 1). As expected, the enamine C¼C bond has (E)-
2
configuration, and the conformation of the bond between the N-atom and the sp -C-
atom is s-trans, so that the styryl group points away from the C-atom bearing the bulky
15
(
silyloxy)(diphenyl)methyl group ). The conformation around the exocyclic C,C bond
is (þ)-synclinal (sc), with one of the Ph groups on top of the five-membered ring and
16
the O-atom in an exo-position. The N-atom is only minimally pyramidalized ), and the
conjugated p-system, including N, C¼C, and Ph, is almost perfectly planar (Fig. 1 and
Entry 1 in Table 1).
There is a slight degree of torsion around the exocyclic NꢀC bond
(
CꢀCꢀNꢀC(2), 1758; CꢀCꢀNꢀC(5), ꢀ 118). Clearly, the Re face of the nucleo-
philic enamine C-atom is like under an umbrella of the (Me SiO)Ph C substituent, with
3
2
the diastereotopic Re Ph group, and especially one of the Me groups at the Si-atom
blocking access of electrophiles from this face, while the Si face is open (see the space-
filling presentation c in Fig. 1). This is in agreement with all experimentally determined
stereochemical courses of reactions involving silyl ethers of diaryl-prolinol as organo-
catalyst [1g][1l][12].
15)
16)
For an in-situ NMR spectrum of the dienamine derived from pent-2-enal and Jørgensenꢂs catalyst
with 3,5-(CF ) -substituted phenyl rings), see supplementary material in [12b].
The N-atoms of N-phenylpyrrolidines are planar (cf. [20]); compound 1 is a vinylogous N-
phenylpyrrolidine. For an aliphatic derivative, we argued in a previous work that it would be
expected to be pyramidalized on the N-atom (see presentation J in [11a], the pyrrolidine ring with
an ꢁobeseꢂ substituent in Table 1, and discussion in Sect. 2.3).
(
3
2

2
004
Helvetica Chimica Acta – Vol. 91 (2008)
Fig. 1. Crystal structure of the enamine 1. a) View of the p-system and the five-membered ring under the
umbrellaꢂ of the (diphenyl)(trimethylsilyloxy)methyl group. b) View of the Re face of the enamine
C(b)-atom. c) View along the plane of the p-system with exposed Si face. Pyramidality on N-atom,
ꢁ
0
.037 ꢄ; torsion angles CꢀCꢀNꢀC(2), 1758; CꢀCꢀNꢀC(5), ꢀ 118; OꢀCꢀCꢀN, 618 (sc-exo). The
black dots indicate the C-atom, at which substituents are attached, as a result of electrophilic attack on
the enamine double bond. Since the inducing stereogenic center C(2) of the pyrrolidine ring has (S)-
configuration the relative topicity (S, Si) of these reactions can be specified as like [21].
2
.2. Iminium Salt 2 (Fig. 2). As in the enamine 1, the p-system is almost perfectly
planar, with hardly any pyramidalization at the N-atom and only a few degrees of
torsion around the N¼C bond (2 – 58) in the two independent molecules of the
asymmetric unit (Fig. 2 and Entry 2 in Table 1). Both, the N¼C and the C¼C bonds are
(
E)-configured, and the conformation of the connecting single bond is s-trans (there
17
would be massive 1,5-repulsion ) in the s-cis conformation!). Similar to the situation
in the enamine 1, where the Me group at Si plays an important role in sterically
hindering access to the nucleophilic C-atom, it is a Ph group at Si of the iminium ion 2,
which contributes substantially to shielding the Re face of the electrophilic C(b)-atom
(compare Fig. 1,b, with Fig. 2,c). To the best of our knowledge, the (methyl)diphe-
nylsilylated diphenyl-prolinol, from which the iminium salt 2 was prepared, has not
been used as an organocatalyst. From the structure reported herein, one might expect
B, R ¼ MePh SiO, to be an especially selective catalyst.
2
2
.3. Discussion of Diphenyl-prolinol Derivatives and Comparison with Calculated
Structures. Besides the new structures of silylated diphenyl-prolinol enamine 1, iminium
salt 2, and of diphenyl-prolinol tetrafluoroborate (Fig. 3, and Entries 1 – 3 in Table 1),
we found 19 crystal structures in the Cambridge File (Entries 4 – 22 in Table 1), 17 of
which contain the prolinol moiety itself (free OH group, Entries 3 – 19), while three are
methylated at the O-atom (Entries 20 – 22). The large majority of the structures has
(
OꢀCꢀCꢀN) gauche conformation around the exocyclic C,C bond, with the OH
group over the five-membered ring (sc-endo; see column heading of Table 1). This
conformation may be the expected one for three reasons: i) there is a stereoelectronic
17)
Here, we use the more general term 1,5-repulsion, rather than A1,3-strain, according to the
terminology used in the textbook by Quinkert, Egert, and Griesinger [23].

Helvetica Chimica Acta – Vol. 91 (2008)
2005
Fig. 2. Crystal structure of the iminium tetrafluoroborate 2. a) Two independent molecules I and II in the
unit cell; the two structures are similar. Pyramidality on N-atom, 0.022/0.027 ꢄ, torsion angles, C-
C¼NꢀC(2), 178/1798; CꢀC¼NꢀC(5), ꢀ 5.5/ ꢀ 5.38; OꢀCꢀCꢀN, 57.2/56.28 (sc-exo). b) View of the
p-system and the pyrrolidine ring of molecule I, with total coverage of the (Si,Re,Re)-face by the
(
Ph MeSiO)Ph C group. c) and d) The Re and the Si face of the electrophilic C-atom of the enoylimino
2 2
system in 2 (molecule I); access of a nucleophile to the diastereotopic Re face is blocked, especially by
one of the Ph groups on Si, while the Si face is wide open.

2
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Helvetica Chimica Acta – Vol. 91 (2008)
Table 1. Selected Parameters from the X-Ray Crystal Structures of the Silyl Derivatives 1 and 2 (Entries 1
and 2, cf. Figs. 1 and 2), and of Diphenyl-prolinols (Fig. 3 and Entries 3 – 19) and Methyl Ethers Thereof
(
Entries 20 – 22). The data in Entries 4 – 22 have been retrieved from the Cambridge Crystallographic
Data File (CCDF) in May 2008. The pyramidality of the N-atom is given as the distance of N from the
plane of its three C-atom bonding partners (in the case of Entries 21 and 22 two C-atoms and a N-atom; D
[
ꢄ], Dunitz parameter; the value for a tetrahedral N is ca. 0.6 ꢄ, cf. Entry 19); all pyramidalizations are
such that the substituent on the N-atom is moving away from the large substituent at C(2) of the
pyrrolidine. When a trigonal C-atom is attached to the pyrrolidine N-atom (Entries 5 – 10), there may be
substantial out-of-plane torsion around this bond (168 in the structure of Entry 6), reducing 1,5-repulsion
1,3
(
A
effect, cf. Footnote 17). The puckering of the pyrrolidine ring varies from structure to structure,
there are envelope and twist conformations, with any of the five ring atoms in distinct positions.
Entry Molecular formula
CCDF Code N-Pyramidality Torsion angles [8]
[
ref.]
D [ꢄ]
CꢀNꢀCꢀC OꢀCꢀCꢀN
sc-endo sc-exo
1
s020507
this work]
0.037
ꢀ 76.8
61.0
[
2
s260308
this work]
0.022
0.027
ꢀ 76.4
ꢀ 79.1
57.2
56.2
[
3
4
s030308
this work]
ꢀ 56.2
[
MIQVEN
3d]
54.6
[

Helvetica Chimica Acta – Vol. 91 (2008)
2007
Table 1 (cont.)
Entry Molecular formula
CCDF Code N-Pyramidality Torsion angles [8]
[
ref.]
D [ꢄ]
CꢀNꢀCꢀC OꢀCꢀCꢀN
sc-endo sc-exo
5
6
XAWLUD
22a]
0.279
0.385
ꢀ 88.4
ꢀ 94.4
ꢀ 46.6
ꢀ 48.7
[
ICOWUS
22b]
0.03
ꢀ 89.2
ꢀ 97.0
87.9
ꢀ 63.6
ꢀ 64.3
ꢀ 47.9
[
7
8
ACULOZ
22c]
0.095
0.131
[
PILQOR
22d]
[
9
PILXEN
22e]
0.136
0.207
ꢀ 84.1
ꢀ 97.0
46.5
[
1
0
CENBED
22f]
ꢀ 64.6
[
1
1
2
KEVTAH
22g]
0.456
0.426
ꢀ 110.1
ꢀ 103.1
ꢀ 54.5
ꢀ 53.3
[
1
GELROE
22h]
[

2
008
Helvetica Chimica Acta – Vol. 91 (2008)
Table 1 (cont.)
Entry Molecular formula
CCDF Code
ref.]
N-Pyramidality
D [ꢄ]
Torsion angles [8]
[
CꢀNꢀCꢀC
OꢀCꢀCꢀN
sc-endo
sc-exo
13
14
15
GELTEW
22h]
0.401
100.5
53.8
[
AQEWEY
22i]
0.462
0.438
105.6
97.2
52.0
48.6
[
SIHZIT
22j]
0.360
116.1
60.6
[
1
6
7
UDEMIA
22k]
0.426
0.445
ꢀ 91.7
ꢀ 49.2
ꢀ 18.8
[
1
ZAQYIZ
22l]
ꢀ 111.8
[
1
8
CEQLIT
22m]
0.256
ꢀ 87.2
ꢀ 98.5
[
1
2
9
0
PESPUY
22n]
0.518
0.421
ꢀ 88.9
ꢀ 59.5
[
INELES
22o]
ꢀ 105.4
ap
178.3
[

Helvetica Chimica Acta – Vol. 91 (2008)
2009
Table 1 (cont.)
Entry Molecular formula
CCDF Code
ref.]
N-Pyramidality
D [ꢄ]
Torsion angles [8]
[
CꢀNꢀCꢀC
OꢀCꢀCꢀN
sc-endo
sc-exo
2
1
2
GIWPIL
22p]
0.148
0.258
ꢀ 82.3
ap
177.4
[
2
HADMOP
22q]
ꢀ 90.7
ap
179.6
[
Fig. 3. X-Ray crystal structure of the HBF4 salt of (S)-diphenyl-prolinol B, Arl ¼ Ph, R ¼ OH. The
OꢀCꢀCꢀN bond has sc-endo conformation (shown in a), with a close distance (2.25 ꢄ) between an NH
H-atom and the O-atom of the OH group (shown in b; sum of Van der Waals radii of H and O, ca. 2.6 ꢄ).
The exocyclic C,C bond is quasi-eclipsed with the neighboring C,H and N,H bonds on a five-ring shape,
which comes close to a twist conformation: torsion angles, NꢀC(2), þ 148; C(2)ꢀC(3), þ 118;
C(3)ꢀC(4), ꢀ 328; C(4)ꢀC(5), þ 408; C(5)ꢀN, ꢀ 348.
preference for the gauche conformation of ethane moieties XꢀCꢀCꢀY (X, Y¼ R N,
2
18
RO, F) ); ii) although there is no clear-cut evidence in the crystal structures (Table 1,
+
Entries 3, 4, and 11 – 17), a geometrically not ideal N ··· HO or NH ··· OH H-bond
would only be possible in a sc-endo-conformation; iii) last but not least, the O-atom
18)
See textbooks on stereochemistry [23][24].

2
010
Helvetica Chimica Acta – Vol. 91 (2008)
19
must be considered smaller than a Ph group ), which should also favor the sc-endo-
conformation (O on top of the pyrrolidine ring) over the sc-exo- and ap-conformations
(
Ph on top of pyrrolidine ring, see Caption of Table 1). Oddly enough, the latter two
conformations, sc-exo and ap, are the ones present in the crystal structures of our two
silyl derivatives (Entries 1 and 2 of Table 1) and in the structures of three MeO
derivatives (Entries 20 – 22), respectively. Whatever the cause for this conformational
change, from sc-endo to sc-exo to ap brought about by putting a silyl or a Me group on
20
the diphenyl-prolinol O-atom, may be ), we can see the geminal-diaryl effect for
conformational fixation and stereodirection in these structures (Fig. 4,a and b).
This effect is exploited throughout the field of stereoselective organic synthesis: the
two Ph or another couple of aryl groups are not only capable of fixing the conformation
around a neighboring single bond, the two aryl groups, which, in a chiral molecule, are
diastereotopic, also become powerful stereodirectors. This is probably best known with
diarylphosphanyl ligands (cf. BINAP (¼1,1’-binapthalene-2,2’-diylbis(diphenylphos-
phane), Fig. 4,c) in transition-metal chemistry [25]. Similarly, the diarylmethanol
groups of TADDOLs (¼a,a,a’,a’-tetraaryl-1,3-dioxolane-4,5-dimethanols) [26] create
two C -symmetrically equivalent chiral pockets for stereoselective reactions and host –
2
guest interactions (Fig. 4,d and e). Another recent example is the modified Evans
auxiliary DIOZ (¼4-isopropyl-5,5-diphenyloxazolidin-2-one; Fig. 4,f), in which the
diastereotopic Ph groups improve functional-group (ꢁchemoꢂ-)selectivity and stereo-
21
selectivity [27] ).
Having a list of experimentally determined diarylmethanol structures (Table 1), we
can make a comparison with calculated structures of this type, with the caveats that a)
crystal packing effects, and/or the position and nature of the counterions in crystalline
salts may cause differences in structural details, and b) that many theoretical
investigations provide gas-phase structures, in which solvent effects are not consid-
22
ered ). Structures of diaryl-prolinol derivatives with unprotected OH group [1w][12a]
23
have been calculated ), but will not be discussed here, because this type of catalyst is
rarely used in organocatalysis.
Of the R SiO derivatives, Jørgensenꢂs catalyst (B, R ¼ Me SiO, Arl ¼ 3,5-
3
3
(
CF ) C H ) was the subject of several computational efforts [12]. Most relevant to
3 2 6 3
15
the X-ray structures of 1 and 2 are the calculated structures of the dienamine ) and of
19)
The A-value (axial/equatorial on cyclohexane) for OH and OMe is between 0.6 and 1.0, the one for
Ph is 2.8 kcal/mol. The Van-der Waals radius of the O-atom is 1.4 ꢄ, the ꢁhalf-thicknessꢂ of a
benzene ring is ca. 1.7 ꢄ [23][24]. The ꢁbarrelꢂ formed by a rotating Ph group has a radius of ca.
3
.2 ꢄ.
20)
21)
A detailed analysis of the conformations around the CꢀPh bonds in these structures might lead to a
rationalization.
Since the parent compound of the TADDOLs was introduced in 1982, numerous articles on ligands
and reagents containing the ꢀ[C(Arl) O]ꢀ moiety were published. For a list of examples, as of the
2
year 2000, see Fig. 19 in [26d] and references cited therein. For a most recent review on TADDOL,
see [26f]. For more general discussions, see [26c –e][28][29]. A substructure search in STN International
data base for the [C(Arl) O] moiety in the period 2000 – 2008 gives thousands of hits.
2
2
2
2
3
)
)
In many cases, the calculations focus on transition-states structures.
The resulting structures all have the sc-endo-conformation of the exocyclic CꢀC bond, as observed
in the crystal structures (Table 1).

Helvetica Chimica Acta – Vol. 91 (2008)
2011
the enoyl-iminium ion shown in Fig. 5 [12b]. The computation with a high level of
24
theory included an estimation of solvation effects ). The similarity of these theoretical
structures and the crystal structures is remarkable. In the iminium salt, all characteristic
values, i.e., pyramidality and torsion angles, are essentially identical (0.025 vs. 0.03 ꢄ,
þ 1788 vs. þ 1798, ꢀ 5.58 vs. ꢀ 68, þ 578 vs. ꢀ 598 (Figs. 1, 2, and 5)). The sign change
in the last value (OꢀCꢀCꢀN) is due to the fact that the silylated O-atom is sc-exo in
the crystal structure and sc-endo in the calculated structure. In the enamine, there are
larger differences: first and foremost, there is practically no pyramidalization of the N-
atom in the crystal structure of the 2-phenylacetaldehyde-derived enamine 1, while the
calculated structure of the pentenal-derived enamine shows an N-pyramidality of
0.21 ꢄ. Thus, theory predicts a structure of the ꢁobeselyꢂ substituted pyrrolidine-
enamine, which was discussed as being most likely responsible for the observed
selectivities, for steric and stereoelectronic reasons [11a]. Why there is no N-
pyramidalization in the crystal structure of the 1-styryl-pyrrolidine 1, while there is
substantial pyramidality in the theoretical structure of an 1-butadienyl-pyrrolidine is
25
difficult to say ). The same is true when we ask the question why, in the crystal
structures of enamine 1 and iminium salt 2, the silylated O-atom is in a sc-exo-
conformation, while the conformation is sc-endo in the corresponding calculated
structures. The four meta-CF groups in Jørgensenꢂs diaryl-prolinol derivatives could be
3
responsible for the structural differences: (CF ) C H is larger than Ph and may not fit
3
2
6
3
in the position on top of the five-membered ring in an sc-exo-conformation (see
Table 1); furthermore, one of the CF groups in both calculated structures is right on
3
top of the p-system, not only extending the steric shielding of the (Si,Re,Si,Re)-face in
the dienamine and of the (Si,Re,Si)-face of the iminium ion, as compared to the
unsubstituted Ph derivative, but also possibly pushing the p-system down, which could
cause pyramidalization on the N-atom of the enamine, but not of the iminium ion (in
which planarity with conjugative stabilization is expected to be much more impor-
tant).
2
.4. Iminium Salts 3 and 4 (Figs. 6 and 7). The p-system of the cinnamaldehyde
derivative 3 (Fig. 6) has (E)-configuration around the C¼N and the C¼C bonds, and s-
trans-conformation around the CꢀC bond; (Z)-configuration would cause 1,5-
t
26
repulsion between one of the Bu Me groups and the 2’-CH group (Fig. 6,b) ).
The plane of the p-system is slightly bent (Fig. 6,a); the Ph group is turned out-of-
plane by 128; there is a slight pyramidalization of the iminium N-atom and torsion
around the C¼N bond (see data in the caption of Fig. 6). A comparison of the
diastereotopic (Re,Re)- and (Si,Si)-faces of the p-system (Fig. 6,c and d) does not
disclose a difference in steric hindrance, which would be nearly as pronounced as in the
case of the diaryl-prolinole derivatives (cf. Figs. 1, 2, and 5). A nucleophilic attack from
2
2
4
5
)
)
CPCM in Gaussian 03, B3LYP/6-316(d)(CPCM)//B3LYP/6-316(d) [12b].
Is conjugation, i.e., N-lone-pair delocalization stronger with the styryl or with the pentadienyl
group? N-Phenyl-pyrrolidine has a planar N-atom (see Footnote 16); there is not much known about
pyrrolidine-enamine structures (see the discussion in [11a]). The barriers to rotation around the
single bond in styrene and in butadiene are similar (ca. 3 and 5 kcal/mol, resp.).
26)
Note that there is 1,5-coplanarity of two Me groups (Me of Bu and MeꢀN) and of a Me and a CH
t
2
t
group (Me of Bu and CH (5)) at distances of 3.2 ꢄ, the Van-der-Waals radius of a Me group being
2
1.8 ꢄ.

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Fig. 4. The geminal-diaryl effect. a) View at the C-atom bearing the two Ph groups and Me Si in enamine
3
1
. b) View along the axis connecting Ph C and Ph Si (CꢀOꢀSi) in iminium ion 2, with a kind of
2
2
staggering of the four Ph groups (cf. e). c) The quasi-axial and quasi-equatorial Ph groups in a BINAP-Pd
complex with room for ꢁapproachesꢂ from the upper left-hand and lower right-hand direction. d) The
similar C -symmetric TADDOL structure with fixed CHꢀC(OH)-bond conformation and drastically
2
different disposition of the diastereotopic Re and Si Ph groups. e) Transduction of the geminal-diaryl
effect on the C-atom to a geminal-diaryl effect on P to give a quasi-staggered arrangement of the eight Ph
groups; note that Pd is four bonds away from the inducing stereogenic centers on the dioxolane ring; use
of this complex for malonate diphenylallylation leads to product of > 99 :1 enantiomer ratio. f)
Superimposition of DIOZ structures demonstrating a buttressing effect of the equatorial Ph on the
CHꢀCHMe -bond conformation and a steric-protection effect upon the C¼O bond in the oxazolidinone
2
18
ring by the quasi-axial Ph group, which is ꢁin the wayꢂ of the Bꢀrgi – Dunitz trajectory ). For leading
references see accompanying text.

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2013
Fig. 4 (cont.)
t
the Si face of the C-atom next to the benzene ring will be hindered by one of the Bu Me
27
groups, especially with bulky reactants (Fig. 6,d) ).
Of the benzyl-trimethyl-imidazolidinone derivative 4 we have, so far, not been able
to obtain single crystals, although samples giving correct elemental analyses were easily
28
prepared. The standard NMR spectrum in (D )acetone ) of the salt 4 (Fig. 7) exhibits
6
one prominent feature: there are two singlets (d 1.88 and 0.90 ppm) from the geminal
1
2
Me groups with a shift difference of ca. 1 ppm; in the precursor C (R ¼ PhCH , R ¼
2
3
R ¼ Me), this difference is ca. 0.06 ppm (d 1.85 and 1.79 ppm). To produce more
detailed structural information, a 2D-NMR spectrum of the iminium salt 4 in
(
D )acetone was recorded, the interpretation of which allows the following conclusions
6
to be drawn: there must be a certain population of a conformer with the benzylic Ph
group facing the cis-Me group, which causes the substantial 1-ppm upfield shift of the
signal from that Me group; the close distance between Ph and Me is also indicated by a
(
very weak) nuclear Overhauser effect (NOE) between the high-field Me H-atoms and
29
the ortho-H-atoms of the Ph group ).
27)
28)
29)
Analysis of successful applications of the Bu-imidazolidinone (BMI [9]) as catalyst (cf. Hantzsch
t
ester) may be compatible [1f][1q][13] with this expectation.
It is surprising that we noticed iminium-ion interchange between cinnamaldehyde and acetone
present in large excess as a solvent) only to a small extent.
It is interesting that, according to an in-situ NMR spectrum in DMSO by Gellman and co-workers
(
1
2
3
[
16], in the enamine from C (R ¼ PhCH , R ¼ R ¼ Me) and 3-phenylpropanal, the shift difference
2
of the two geminal Me groups is 0.5 ppm (Fig. 7,c).

2
014
Helvetica Chimica Acta – Vol. 91 (2008)
Fig. 5. DFT-Calculated structures of a dienamine (cf. Fig. 1) and of an a,b-unsaturated iminium ion (cf.
Fig. 2) derived from the silylated diaryl-prolinol with 3,5-bis-trifluoromethylated Ph groups [12b]. a)
Dienamine of pentenal: pyramidality of N-atom, 0.214 ꢄ, torsion angles, C¼CꢀNꢀC(2), ꢀ 1678;
C¼CꢀNꢀC(5), ꢀ 188; OꢀCꢀCꢀN, ꢀ 688 (sc-endo), s-trans-conformation of the exocyclic NꢀC
bond. b) Iminium salt of pentenal: pyramidality of N-atom, 0.03 ꢄ, torsion angles, CꢀC¼NꢀC(2), 1798;
CꢀC¼NꢀC(5), ꢀ 68; OꢀCꢀCꢀN, ꢀ 598 (sc-endo), (E)-configuration around the N¼C bond.
Compare with the values in the corresponding X-ray structures in Figs. 1 and 2.
2
.5. Comparison of the X-Ray and NMR Structures of the Iminium Ions 3 and 4 with
Analogous Computed Imidazolidinone Structures. To the best of our knowledge, the
most extensive, highest-level DFT calculations of structures and reaction transition
states involving imidazolidinones as organocatalysts have been published by Houk and
1
2
co-workers [14]. The iminium ions from the two key imidazolidinones C, R ¼ Bn, R ¼
3
1
2
t
3
R ¼ Me, and cis-C, R ¼ Bn, R ¼ Bu, R ¼ H, and but-2-enal, and their reactions with
pyrroles and indoles were computed in the gas phase and in H O. The higher
selectivities observed experimentally [31] with the Bu derivative were confirmed
2
t
theoretically. The most stable structures of the two iminium ions obtained in the
calculations are shown in Fig. 8.
Clearly, and not surprisingly, the Re C(2)/Si C(3)-face of the electrophilic double
bond is subject to more severe steric hindrance than the diastereotopic Si C(2)/Re
C(3)-face. As with the diaryl-prolinoles (Sect. 2.3), the similarity between the
computed structures (Fig. 8), and the NMR and X-ray structures (Figs. 6 and 7) is

Helvetica Chimica Acta – Vol. 91 (2008)
2015
Fig. 6. Crystal structure of iminium tetrafluoroborate 3. The (S)-form is shown; for the measurement a
racemate crystal was used. a) View of the molecule along the plane of the p-system. b) View at ion 3 with
t
a Newman projection along the BuꢀC(2) bond; the red arrow indicates the area of severe 1,5-repulsion
in the diastereoisomer with (Z)-configuration of the exocyclic N¼C bond; the black arrows indicate two
1,5-repulsions in this and other 2-(tert-butyl)-imidazolidinones (see discussion in Sect. 2.5). c) and d)
View of the diastereotopic (Re,Re)- and (Si,Si)-face of the C¼C bond. Pyramidality of the iminium N-
atom, 0.07 ꢄ, torsion angles, CꢀC¼NꢀC(2), þ 1778; CꢀC¼NꢀC(5), þ 88.
striking. In the most-stable calculated structure of the benzyl-dimethyl-derivative
(
Fig. 8,a ), there is an interaction between the benzene ring of the 5-Bn group and the
1
cis-2-Me group (distance between the C-atom of the Me group and the center of the
aromatic ring 3.8 ꢄ), compatible with the shielding of that Me group in the NMR
spectrum of the BF salt 4 (see Sect. 2.4 and Fig. 7). Also, fine details of structural
4
distortions around the iminium N-atom (pyramidality, torsion angles) found in the

2
016
Helvetica Chimica Acta – Vol. 91 (2008)
Fig. 7. Selected NMR data of 5-benzyl-2,2,3-trimethylimidazolidin-4-one derivatives. Me Region of the
1
1
2
3
H-NMR spectra of the imidazolidinone C (R ¼ Bn, R ¼ R ¼ Me) HBF salt (a), of the iminium salt 4
4
(
b) in acetone, and of the corresponding enamine signals (c) in an in situ spectrum in DMSO [16], as well
1
2
3
as X-ray crystal structure of the HCl salt of the imidazolidinone C (R ¼ Bn, R ¼ R ¼ Me) (d) [30]. An
ꢀ
ꢀ
4
in situ NMR spectrum of the salt 4, Cl instead of BF , (in CD OD) has been described in the
3
supplementary material of a recent work [17a]. The shielding of the diastereotopic Re Me group by the
aromatic ring in 4 but not in the precursor is evidence for the population of a conformation as shown in
Fig. 8,a , for the computed crotonaldehyde-derived iminium salt.
1

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Helvetica Chimica Acta – Vol. 91 (2008)
crystal structure are predicted by 2004-DFT computations of Houk and co-workers [14]
see the comparison in Table 2).
(
3
. Lessons from the Structures of N-Acyl-imidazolidinones. – There are some
interesting aspects about the configurational stability of the iminium ions derived from
imidazolidinones. It is known that such iminium ions can undergo deprotonation in the
a-position to C¼O with formation of azomethine ylides (Eqn. 1 [32]). If this would
happen in applications of imidazolidinones as organocatalysts, there would be
racemization of the benzyl-dimethyl derivative (Eqn. 2) and epimerization of the
benzyl-(tert-butyl) derivative (Eqn. 3). This should cause deterioration of enantiose-
lectivity as the reactions proceed. An ylide derived from BMI, on the other hand, could
lead to loss of catalyst by reactions with added nucleophiles, for instance, in 1,3-dipolar
cycloadditions (cf. Eqn. 1). We are not aware of reports about such problems with the
imidazolidinone catalysts. There may be good reasons for the phenylalanine-derived
ylides not being formed readily: the deprotonation would push the benzylic CH group
2
in-plane with the 2’-CH group causing 1,5-repulsion, as indicated in the ylide Formulae
in Eqns. 2 and 3. Furthermore, the deprotonation/protonation equilibrium shown in
Eqn. 3 is expected to occur with retention of configuration at C(5) for kinetic and
t
thermodynamic reasons: protonation of the ylide from the face trans to the Bu group
should be sterically favored, and the cis-iminium ion ought to be more stable than the
trans-isomer. What makes us confident about such statements? It is the lesson we

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2019
Table 2. Comparison of DFT-Calculated [14] with Measured Distortions around N(1) of Imidazolidi-
none-Derived Iminium Ions. For definitions, see Table 1. For the corresponding structures, see Figs. 6 and
8. In all cases, pyramidalizations are such that N(1) moves out of plane of its three bonding partners
towards the substituents in 2- and 5-position of the heterocyclic ring (see the ꢁexaggeratedꢂ presentations
I – III). Note that the signs of the torsion angles reverse when we go from b to 3, because the absolute
configuration of C(2) is opposite in the two structures. Cf. also the presentations b, d, and e in Fig. 9.
Conformation
Pyramidality
D on N(1) [ꢄ]
Torsion angles [8]
CꢀCꢀNꢀC(2)
CꢀCꢀNꢀC(5)
a1/a3
a2
0.023
0.042
ꢀ 174.2
2.3
ꢀ 1.3
ꢀ 174.9
calculated (Fig. 8)
b /b /b
3
calculated (Fig. 8)
0.115
ꢀ 172.7
ꢀ 10.0
1
2
0
.067
177.5
7.9
measured X-ray
structure of 3 (Fig. 6)
30
learned a long time ago from investigations of acyl-imidazolidinones ), and, after all,
there is a resemblance between an N-acyl-imidazolidinone F and an imidazolidin-
iminium ion G.
Imidazolidinones of type C were first employed in organic synthesis for the
preparation of a-branched amino acids [7c], in a process, which was termed ꢁself-
31 32 33
regeneration of stereogenic centersꢂ (SRS; Eqn. 4) ) ) ). With the chiral glycine
30)
For review articles, see [7c][8]. An electronic version of the article ꢁEPC Syntheses with C,C-Bond
Formation via Acetals and Enaminesꢂ (Modern Synthetic Methods 1986) [8a] can be obtained from
D. S. upon request.
For recent approaches, see the review article by Vogt and Brꢁse [33].
Originally, we used the term ꢁself-reproductionꢂ [7a], but our late colleague V. Prelog convincingly
argued that this term should be reserved for biology.
3
3
1
2
)
)
33)
For a recent article on this subject, see [34].

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Helvetica Chimica Acta – Vol. 91 (2008)
derivative 2-(tert-butyl)-3-methylimidazolidin-4-one (BMI) [9] the method was
extended (Eqn. 5). Early on, it was noticed that the cis-2,5-disubstituted imidazolidi-
nones and related heterocycles became thermodynamically more stable than the trans-
isomers, when the N-atom was acylated. Thus, the imines from amino acid N-methyl-
amides and pivalaldehyde cyclize to the trans-imidazolidinone (unsubstituted in the 1-
position) under acid catalysis in the cold, while, upon heating with benzoic anhydride,
34
cis-1-benzoylimidazolidinones are the major product (70 – 90%) [7c] (Eqn. 6) ).
There are numerous reports pointing to the higher stability of cis-2,5-disubstituted N-
acyl-imidazolidine, oxazolidine, and thiazolidine derivatives, as compared to their
trans-isomers [7b][7c][8][35] (see, e.g., the trans-cis isomerizations in Eqn. 7 and 8
[
36]). As discussed previously and as outlined in Fig. 9 and Table 3, the higher stability
of cis-isomers may be attributed to minimalization of 1,5-repulsions, i.e., to ꢁthe power
1,3
of the A -effectꢂ [8][37]. Pyramidalizations and relevant torsion angles of some trans-
,5-disubstituted imidazolidinones are collected in Table 3 (Entries 5 – 11 and 15 – 17);
2
as can be seen, things for reduction of 1,5-repulsion look even grimmer in 2,5,5-
t
trisubstituted (Entries 12 – 14 and 18) 2- Bu-imidazolidinones and in derivatives with a
substituent at a trigonal C(5)-atom (Entries 19 – 21).
In the simpler BMI derivatives, carrying a substituent only in the 2-position of the
t
imidazolidinone ring, 1,5-repulsion is still at work: upon N-acylation, the Bu group,
which is quasi-equatorial in BMI itself, becomes quasi-axial. This causes an increased
t
steric shielding of the face of the ring and of the exocyclic p-system, on which the Bu
group resides. This is evident from the X-ray crystal structures of Boc-BMI and Bz-
BMI, which we have now been able to determine (Figs. 10 and 11), and from the
comparisons with the prototypical proline case and with the iminium salt 3 in Fig. 12.
4
. Conclusions and Outlook. – The combinatorial preparation of diaryl-prolinol-
and imidazolidinone-derived organocatalysts opens the entry to a wide variety of
34)
In the MacMillan procedure for preparing the cis-benzyl-(tert-butyl) derivative, a ca. 1:1 cis/trans-
mixture is obtained (under thermodynamic conditions) and separated chromatographically [10c].

Helvetica Chimica Acta – Vol. 91 (2008)
2021
structurally related systems for substrate-adjusted optimization of the catalysis
Scheme 1). As shown previously [11a] and in the present work, the reactive
(
intermediates of this catalysis can be isolated and characterized by conventional
preparative and spectroscopic methods. X-Ray crystal structures and NMR spectra of
enamines and iminium ions derived from the catalysts may provide structural details

2
022
Helvetica Chimica Acta – Vol. 91 (2008)
Fig. 9. Crystal structures of cis- and trans-2,5-disubstituted imidazolidin- and oxazolidin-4-ones (f and g,
resp.). Pyramidalization of the acylated N-atom, torsion around the NꢀCO bond, quasi-axial
arrangement of the two substituents, and proper folding of the five-membered ring lead to minimal-
ization of 1,5-repulsion (indicated in a – e). In the cis-disubstituted heterocycles, such as the one shown in
f [35d][38], pyramidalization on N-atom puts the substituents on the carbonyl C-atom closer to the
neighboring H-atoms, away from the substituents (b and f). In almost all structures of this type, the
t
smaller C¼O O-atom (short C¼O bond, no substituents) is syn to the Bu group, and rotation around the
amide bond can further relieve conformational strain (see also Table 3). In the computed iminium salt
(
(
compare Fig. 8,b, with f shown here), this pyramidalization and rotation is less pronounced
energetically more ꢁcostlyꢂ). In the less stable trans-isomers, such as that shown in g [37], the degree
of pyramidalization is also smaller; it would increase 1,5-repulsion on one side and decreases it on the
other side; rotational deformation, as shown in e, on the other hand, can lead to decreased 1,5-repulsion
(cf. Table 3). The dominant common theme in all structures of this type is minimalization of 1,5-
interaction. For a complete collection of X-ray structures of monocyclic 1-acyl-3-alkyl-1,3-imidazolidin-
4
-ones, we refer to the CCDF. Note that in N-acyl-piperidines the 1,5-repulsion forces 2- and 6-
substituents into the axial position of chair conformations (see the discussion in [37]).
relevant to their reactivities (Figs. 1, 2, 6, and 7). In the diaryl-prolinol derivatives, the
powerful stereodirecting effect of the geminal diaryl moieties is dominant (Fig. 4 and
Table 1). In the imidazolidinone derivatives, minimalization of 1,5-repulsion around
the exocyclic N¼C bond at the stage of iminium-ion formation is decisive, whereby the
steric shielding of one face of the forming p-system is increased (Fig. 12).

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Table 3. Pyramidalizations and Torsion Angles in Selected Monocyclic 2-(tert-Butyl)-3-methyl-1,3-imidazolidin-4-ones
and Silyl-enolethers in X-Ray Crystal Structures, Testifying the Distortions around the Exocyclic Amide Bonds. The
values for the new structures are shown in Entries 1 – 3 (cf. Figs. 6, 10, and 11). In the Formulae, the conformation
around the exocyclic amide bonds are drawn as found in the crystal structures, i.e., mostly s-cis with the C¼O O-atom on
t
the side of the Bu group (exceptions in Entries 5, 13, 14, and 19). For better recognition of the kind of distortion, see the
Newman-type presentations in the caption of Table 2 and in Fig. 9. There is less or hardly any pyramidalization of N(1)
in the trans-disubstituted structures (Entries 5 – 11; cf. Fig. 9,
d and e). The torsion angles around the
t
C(exo)ꢀNꢀC(2)ꢀC( Bu) is between 80 and 908, but can be as large as 1178 in a ꢁcase of emergencyꢂ (Entry 19).
From the generally small sizes and the signs of the O¼CꢀNꢀC(2) torsions, it appears that the ꢁsmallerꢂ C¼O O-atom
causes less 1,5-strain than an OR O-atom or a Ph group.
Entry Molecular formula CCDF Code N-Pyra-
Torsion angles [o]
[
ref.]
midality
D [ꢄ]
t
CꢀNꢀCꢀC( Bu) CꢀCꢀNꢀC(2)
CꢀCꢀNꢀC(5)
O¼CꢀNꢀC(5)
O¼CꢀNꢀC(2)
OꢀCOꢀNꢀC(2) OꢀCOꢀNꢀC(5)
1
[this work]
0.067
91.5
177.5
–
–
7.9
–
–
2
[this work]
0.213
0.233
105.9
108.1
–
13.2
67.0
–
ꢀ 161.6
18.6
ꢀ
1
3
4
[this work]
VURBIT
172.8
9.4
–
27.1
ꢀ 155.1
–
ꢀ
[
39a]
5
NAHSEV
39b]
0.097/0.112
90.4/89.5
–
–
[
ꢀ 172.1/ ꢀ 170.3
22.4/26.4
ꢀ 157.2/ ꢀ 153.6
8
.4/9.7

2
024
Helvetica Chimica Acta – Vol. 91 (2008)
CCDF Code N-Pyra- Torsion angles [o]
Table 3 (cont.)
Entry Molecular formula
[
ref.]
midality
D [ꢄ]
t
CꢀNꢀCꢀC( Bu) CꢀCꢀNꢀC(2)
CꢀCꢀNꢀC(5)
O¼CꢀNꢀC(5)
O¼CꢀNꢀC(2)
OꢀCOꢀNꢀC(2) OꢀCOꢀNꢀC(5)
6
7
8
9
NAHRUK
39b]
0.117
0.092
0.071
0.103
0.172
89.1
–
2.6
175.9
–
ꢀ 159.9
21.5
[
ꢀ
ꢀ
NAHSOF
39b]
84.3
–
6.0
172.4
–
ꢀ 160.2
21.3
[
PATCAO
39c]
ꢀ 84.4
–
–
[
ꢀ 10.8
158.7
ꢀ 20.5
1
70.1
JOPWUG
37]
83.5
–
10.6
66.8
–
ꢀ 154.0
28.6
[
1
1
0
LAXXIR
36c]
88.6
–
2.0
177.4
–
ꢀ 152.6
28.1
[
ꢀ
1
1
2
JOPXAN
37]
0.007
0.209
ꢀ 78.7
–
ꢀ 16.4
63.9
–
[
162.9
ꢀ 17.2
1
1
NAHSIZ
39b]
90.6
–
–
ꢀ 151.5
30.7
[
ꢀ 1.4
ꢀ
179.3

Helvetica Chimica Acta – Vol. 91 (2008)
CCDF Code N-Pyra- Torsion angles [o]
2025
Table 3 (cont.)
Entry Molecular formula
[
ref.]
midality
D [ꢄ]
t
CꢀNꢀCꢀC( Bu) CꢀCꢀNꢀC(2)
CꢀCꢀNꢀC(5)
O¼CꢀNꢀC(5)
O¼CꢀNꢀC(2)
OꢀCOꢀNꢀC(2) OꢀCOꢀNꢀC(5)
13
14
NAHSAR
39b]
0.141
88.6
–
–
20.8
ꢀ 158.7
[
ꢀ 179.7
0
.8
NAHSUL
39b]
0.134
84.7
–
–
25.0
ꢀ 155.4
[
ꢀ 174.6
.9
4
15
16
17
18
19
HEVTIL
39d]
0.101
0.206
0.179
0.237
0.281
ꢀ 87.3
93.5
165.5
ꢀ 10.4
–
ꢀ 29.7
154.4
–
[
RIQCEZ
39e]
ꢀ 175.9
ꢀ 0.5
–
34.1
ꢀ 150.6
–
[
RIQCAV
39e]
94.6
ꢀ 173.2
33.1
ꢀ 150.6
–
[
3.1
–
SOSDEJ
39f]
ꢀ 90.8
ꢀ 116.9
168.1
ꢀ 7.7
–
ꢀ 45.8
138.4
–
[
JOPXER
37]
–
–
[
ꢀ 148.6
ꢀ 9.5
3
2.6
171.7

2
026
Helvetica Chimica Acta – Vol. 91 (2008)
Table 3 (cont.)
Entry Molecular formula CCDF Code N-Pyra- Torsion angles [o]
[
ref.]
midality
D [ꢄ]
t
CꢀNꢀCꢀC( Bu) CꢀCꢀNꢀC(2)
CꢀCꢀNꢀC(5)
O¼CꢀNꢀC(5)
O¼CꢀNꢀC(2)
OꢀCOꢀNꢀC(2) OꢀCOꢀNꢀC(5)
2
0
1
JIMHOC
39g]
0.287
0.211
108.4
102.9
–
–
ꢀ 154.8
27.3
[
ꢀ 17.1
1
64.9
2
JIMHIW
39g]
158.5
ꢀ 23.1
–
10.7
ꢀ 171.0
–
[
The same effect is operative with N-acyl-imidazolidinones, in which the partial
double-bond character of the exocyclic amide bond causes 1,5-repulsive interactions;
these are minimized by more pronounced distortions (N-pyramidalization and out-of-
plane rotation around the amide bond) than those seen in a crystal structure of an
imidazolidinone-derived iminium salt (Figs. 6 and 9 – 12, and Table 3). It is pointed out
that the same kind of effect is responsible for the very special role proline plays as
structural element in proteins. The structural similarities are demonstrated, once more,
by the comparison outlined in Fig. 13, wherein three additional types of N-acylated
heterocycles of synthetic importance are shown, the Mutter pseudo-prolines (y-Pro)
[
41], the Evans-type auxiliaries [27][42], and the Garner aldehyde [43].
The experimentally determined structures and NMR spectra are also compared
with structures obtained by high-level-of-theory DFT computations (Figs. 5 and 8, and
Table 2). This comparison reveals striking agreement of delicate structural details
35 36
between measured and calculated systems ) ). In fact, structural effects predicted by
theory were now confirmed by experiment. The same type of DFT investigations, for
3
3
5
6
)
)
For recent calculations of the intermediates in proline catalysis, see [11c].
In a seminal work, Platts, Tomkinson, and co-workers used rac-2-(trifluoromethyl)pyrrolidine ·
HPF6 as a Diels – Alder catalyst and obtained the same endo/exo-selectivity as with isolated
iminium salt. A superimposition of the X-ray crystal structure and DFT-calculated structure ꢁshows
much similarityꢂ [44].

Helvetica Chimica Acta – Vol. 91 (2008)
2027
Fig. 10. X-Ray crystal structure of 1-(tert-butoxycarbonyl)-2-(tert-butyl)-3-methyl-1,3-imidazolidin-4-
t
one (Boc-BMI). a) View at the carbamate and ring plane from the face cis to the Bu group. b) View at
t
t
the ring plane trans to the Bu group. c) and d) 1,5-Repulsive Van der Waals contact between Bu Me
groups, and the N(3)ꢀCH and CH (5) group, C,C-distances 3.20 and 3.28 ꢄ, respectively (see arrows).
3
2
e) and f) The views along the OCꢀN axis and along the average ring plane of the heterocycle show the
pyramidality of N(1), with reduction of 1,5-repulsion.

2
028
Helvetica Chimica Acta – Vol. 91 (2008)
Fig. 11. X-Ray crystal structure of 1-benzoyl-2-(tert-butyl)-3-methyl-1,3-imidazolidin-4-one (Bz-BMI).
t
a) View at the amide and heterocycle plane from the face cis to the Bu group. b) View along the
exocyclic amide bond with pyramidal N(1) and a slight torsion around this bond. c) One face of the
t
heterocycle is sterically shielded by the Ph group, the other by one of the Bu Me groups (cf. ꢁProtecting
Groups are not Just Passive Spectatorsꢂ, Scheme 33 in [8b] and [40]).
instance, by Houk and co-workers [14], have been also applied to transition-state
structures, to reproduce experimentally determined levels of reaction stereoselectiv-
37
ities (relative energies of transition states, even including solvent effects) ). With the
power of computing increasing exponentially in recent years, one is tempted to raise the
question when synthetic organic chemists will start carrying out calculations to choose
38
the best organocatalyst ) for a certain reaction before they go to the laboratory, with a
good chance of avoiding tedious experimental optimizations.
All experimental details of the work mentioned herein will be published in a
forthcoming work, together with results of our ongoing investigations in this field, for
37)
For application of a new program (ACE ¼ Asymmetric Catalyst Evaluation), which is faster
requiring less computing power) than DFT calculations, to 44 known ꢁsystemsꢂ (Diels – Alder and
(
aldol additions), see [45]. The experimental results are reproduced to a reasonably high degree of
accuracy. Title of the work: ꢁToward a Computational Tool Predicting the Stereochemical Outcome
of Asymmetric Reactionsꢂ.
Organocatalysts, by definition, work in the absence of metal derivatives, i.e., essentially only main-
group elements (C, H, N, O, P, S, halogen) are involved in the calculations of ꢁarrow-pushingꢂ
reactions. For these elements, the DFT calculations appear to be especially successful. The situation
with reactions catalyzed by transition-metal complexes is far more complex [46][47].
38)