Design of a conformationally rigid hydrazide organic catalyst

Article abstract of DOI:10.1002/adsc.200600268

Conformational control was utilized to design a hydrazide organocatalyst for asymmetric Diels-Alder reactions, thus introducing a new aspect to organocatalysis. Diastereoselectivities and enantioselectivities of up to 96 % were achieved by the application

Full text of DOI:10.1002/adsc.200600268

UPDATES
DOI: 10.1002/adsc.200600268
Design of a Conformationally Rigid Hydrazide Organic Catalyst
Mathieu Lemay,a Livia Aumand,a and William W. Ogilviea,*
a
Department of Chemistry, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
Fax : (+1)-613-562-5170; e-mail: wogilvie@science.uottawa.ca
Received: June 7, 2006; Published online: January 8, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Conformational control was utilized to
design a hydrazide organocatalyst for asymmetric
Diels–Alder reactions, thus introducing a new
aspect to organocatalysis. Diastereoselectivities and
enantioselectivities of up to 96% were achieved by
the application of the rigidified catalyst. The first
crystal structure of a key iminium intermediate in
an organocatalyzed process is also provided.
rigid hydrazide-based catalyst. Absolute proof of the
structure of a reactive iminium intermediate has been
obtained by a crystal structure that provides valuable
information on the key enantiodetermining step. Su-
perior yields and selectivities have been obtained
using rigidified catalyst 10 as exemplified in the enan-
tioselective Diels–Alder[8] reactions mediated by this
compound.
Condensation of catalyst 1 with aldehyde 2 results
in the formation of iminium ions that can adopt one
of two key geometries (3 and 4), as established by
1H NMR.[6] The structures of these reactive iminiums
can account for the enantioselectivity observed in the
asymmetric Diels–Alder reaction.[9] As shown in
Scheme 1, cis-iminium 3 leads to the major enantio-
Keywords: aldehydes; conformational control; cy-
cloaddition; hydrazides; organic catalysis
Catalysts designed to mimic the asymmetric qualities mers 6 and 7 through bottom-face approach of the
of enzymes have resulted in a rich literature.[1] Many diene. Stereochemical bias is provided in this struc-
laboratories have examined the catalytic role of ture by the steric bulk of the camphor bridgehead
simple organic molecules in a variety of organic reac- methyl groups that impair top-face approach of the
tions[2] that have been thoroughly illustrated by the diene. trans-Iminium 4 leads to the minor enantio-
scope of chemistry catalyzed by the amino acid pro- mers 8 and 9 through a process that also invokes
line.[3]
Proteins and peptides adopt conformations which
allow them to mediate biological processes with a
high degree of selectivity. Lacking the long-range in-
teractions found in macromolecules, smaller mole-
cules rely more heavily on local conformations to ach-
ieve selectivity in synthetic transformations. This has
been successfully demonstrated through the synthesis
of non-natural peptides, in which a change in confor-
mational behavior can alter the catalytic activity.[4]
Small-molecule catalysts have the potential to bridge
the link between synthetic and natural catalysts
through the incorporation of elements such as confor-
mational restraints.[5] A better understanding of such
interactions within a catalytic entity could facilitate
the design of small organic catalysts.
We recently described the design and synthesis of a
new hydrazide-based organic catalyst that accelerates
Diels–Alder reactions in water[6] and investigated the
mechanism in detail.[7] Based on information gained
in those studies, we now describe structural modifica-
tions that have produced the first conformationally additions catalyzed by hydrazide 1.
Scheme 1. Origin of enantioselectivity in Diels–Alder cyclo-
Adv. Synth. Catal. 2007, 349, 441– 447
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
441

Mathieu Lemay et al.
UPDATES
Table 1. Effect of substituents on the side chain of hydrazide catalysts in asymmetric Diels–Alder reactions.
Entry[a]
R
Yield [%][b]
exo:endo (6:7)
ee (exo/endo)[c]
1CH
2Ph
96
1.9:1
90/88
2
3
4
5
CH2(3,5-dimethylph.8e:n1y8l)9/87
CH2-naphthyl
CHPh2
911
82[d]
32
1.7:1
1.6:1
1.1:1
77/74
75/58
6/7
C
A
10
[a]
Reactions performed at 1M in water using 20 mol% of catalyst and TfOH.
Combined isolated yield.
Enantiomeric excess determined by chiral GLC.
HClO4 was used in place of TfOH.
[b]
[c]
[d]
bottom-face approach of the diene. This analysis sug- chain was closer to the iminium moiety than was the
gests that enantioselectivity is a consequence of the phenyl ring. Given that the benzyl group could freely
À
position of the benzyl side-chain of the catalyst that rotate about the C N bond, it was apparent that alter-
dictates the energy of transition states arising from nate, undesired catalyst conformations were being ac-
trans-iminium 4. One could therefore postulate that cessed. The benzyl group of the catalyst could be di-
structural changes that favor cis-iminiums such as 3 rected away from the iminium moiety in these con-
would lead to a corresponding increase in the formers allowing space for the undesired trans-imini-
amounts of 6 and 7 resulting in higher enantioselectiv- um 4 to form resulting in lower enantioselectivities.
ities. This could be most easily accomplished through
To investigate this effect, a dihedral driver study
destabilization of trans-iminium 4 and, consequently, was conducted using PM3 semi-empirical methods.[10]
the transition states involved in forming 8 and 9. The The dihedral angle between the hydrazide nitrogen
À À À
structure of 4 suggested that simply increasing the and benzyl side-chain (C C N CO) was altered sys-
size of the benzyl group would destabilize this imini- tematically in 308 increments and at each fixed dihe-
um relative to 3.
dral angle, the energy of the conformer was mini-
Armed with this hypothesis, we tested several cata- mized and the energy plotted as a function of the di-
lysts with large side chains (Table 1). The introduction hedral angle.
of methyl groups onto the phenyl ring of the benzyl
This analysis revealed the presence of two energy
group or the use of a large planar naphthyl unit at minima at dihedral angles of approximately 1508 and
this position did not increase selectivity relative to the 2708 as depicted in Figure 1. The energy barrier be-
benchmark benzyl side-chain when catalyzing the cy- tween these conformers was on the order of
cloaddition of cinnamaldehyde and cyclopentadiene ~2 kcalmolÀ1, in principle permitting rotation about
À
(entries 1–3). Bulkier substituents such as a diphenyl- the C N bond. The 1508 conformer (3 1508) posi-
methyl or tert-butyl group led to reduced selectivity tioned the phenyl ring in close proximity to the imini-
and reactivity presumably due to increased sterics um moiety thus inhibiting the formation of undesired
during iminium formation (entries 4 and 5).
trans-iminium 4. This conformer would be expected
Since simple steric modifications to the benzyl side- to show selectivity for the major enantiomers 6 and 7
chain did not improve the facial selectivity of the pro- during the Diels–Alder process. In contrast, the 2708
cess, a more detailed understanding of the catalyst be- (3 2708) conformer could create a void in proximity to
havior was sought. NOESY analysis of the major imi- the iminium moiety. This structural gap could in prin-
nium 3[6] showed a strong correlation between the ciple accommodate trans-iminium structures similar
iminium proton and the neighboring benzylic hydro- to 4 resulting in stereochemical erosion. This study
gens, thus confirming the cis-iminium geometry (see suggested that conformational restraints on the cata-
box Scheme 1). The interaction between the iminium lyst side-chain to disallow conformers similar to
and aromatic protons was considerably weaker rela- 3 2708 would produce an increase in enantioselectivity
tive to that of the iminium and benzylic protons sug- by raising the energy required to access transition
gesting that the methylene unit of the benzyl side- states and iminiums related to 4.
442
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 441– 447

Design of a Conformationally Rigid Hydrazide Organic Catalyst
UPDATES
À À À
Figure 1. Plot of the energy surface of iminium 3 generated from catalyst 1 as a function of the C C N CO dihedral angle.
This could be accomplished through the introduc-
An analysis of 13 (derived from 11) produced sig-
tion of conformational control that would ensure ex- nificantly different results as three conformers were
clusive access to conformers. To accomplish this re- sampled at 608, 21 08 and 2708 suggesting that minimal
striction, the delocalized nature of the hydrazide link- conformational selection would occur. The lowest
age could be exploited to provide 1,3-allylic strain by energy conformer was found to occur at 2708, provid-
the incorporation of a stereogenic centre on the ben- ing considerable space to accommodate a trans-imini-
zylic side-chain to act as a conformational lock. With um moiety and suggesting that 11 would yield lower
the introduction of a new stereogenic centre, two pos- enantioselectivities in the Diels–Alder cycloaddition
sible catalysts 10 and 11 could be envisaged relative to catalyst 1.
(Figure 2).
Compounds 10 and 11 were synthesized and tested
in the Diels–Alder cycloaddition between cinnamal-
dehyde and cyclopentadiene. The use of catalyst 10
maintained excellent yields while providing superior
diastereoselectivities and enantioselectivities relative
to catalyst 1 (Table 2, entries 1and 2). As anticipated
the mismatched catalyst 11 proved to be inferior to
the original catalyst in this cycloaddition process
(entry 3). The improvements in both exo/endo ratio
and enantioselectivity gained from using conforma-
Dihedral driver investigations were done on the tionally rigid catalyst 10 were consistent for other sub-
iminiums that would be formed from both of these strates. Using 4-nitrocinnamaldehyde as the dieno-
diastereomers to clarify the conformational profile of phile resulted in enantioselectivity increases when
each. We were pleased to find that iminium 12 (de- using catalyst 10, giving an enantiomeric excess of
rived from 10) experienced one large energy mini- 96% for the exo isomer (entries 4 and 5). The corre-
mum near the dihedral angle of 1508 suggesting that a sponding 2-substituted dienophile enjoyed similar im-
significant part of the population would exist as provements producing an ee of 94% for the exo
12 1508 (Figure 3). At 1508 the benzylic hydrogen was isomer (entries 6 and 7). Catalyst 10 produced a simi-
approximately syn-periplanar to the hydrazide car- lar improvement when used together with crotonalde-
bonyl as anticipated by allylic-type strain, and the hyde as the ee increased by 14% over the results ob-
phenyl moiety was properly positioned to interfere tained with catalyst 1 (entries 8 and 9).
with the formation of undesired trans-iminiums such
We crystallized catalyst 10 whose X-ray structure
as 4. Thus, 10 would be expected to be a more selec- gave information about the electronic properties of
tive catalyst than 3.[11]
the hydrazide ring. One striking factor was the hy-
bridization of the N-4 which was trigonal planar. This
Adv. Synth. Catal. 2007, 349, 441– 447
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
443

Mathieu Lemay et al.
UPDATES
Figure 2. Plots of the energy surfaces of iminiums 12 and 13, generated from catalysts 10 and 11 respectively, as a function of
À À À
the C C N CO dihedral angle.
rived from 10 and 2, was prepared in 5% H2O/
CH3NO2 and crystallized from THF to provide mate-
rial for X-ray analysis (Figure 3).[13] To our knowledge
this is the first reported example of the crystallo-
graphic structure of an iminium intermediate in an or-
ganocatalyzed cycle.[14]
The hydrazide-iminium p system was completely
conjugated in this structure, from the hydrazide car-
bonyl to the aromatic ring of the dienophile, as indi-
cated by the complete planarity of the system. The
À
N CO bond was slightly elongated, relative to 10,
from 1.36 Š to 1.39 Š, and the N N bond was slightly
À
shortened from 1.43 Š to 1.41 Š. The small reduction
Figure 3. X-ray structures of hydrazide catalyst 10 and of in-
termediate iminium 12 (triflate anion omitted for clarity).
in delocalization this implied could be explained by
the fact that the “amide” nitrogen must donate more
of its electron density, relative to 10, to compensate
for the newly generated positive charge.
could be rationalized by resonance into the carbonyl
Within the crystal lattice, the iminium molecule 12
group in addition to delocalization arising from align- showed close contacts to the triflate counterions
À
ment of the N N lone pairs, consistent with an alpha- within a distance allowable for C-H O hydrogen
effect.[12] This was corroborated with our previous ob- bonding.[15] The triflate anion is a non-coordinating
servations that hydrazide catalyst 10 was much more ion and the likelihood of such hydrogen bonding oc-
reactive toward iminium formation than other catalyt- curring in aqueous solution with this ion was expected
ic amine systems.[6,7]
to be negligible. Variable temperature and concentra-
1
The ability of hydrazide catalysts to rapidly and tion H NMR experiments performed on 12 showed
completely generate iminium ions prompted us to try no significant chemical shift changes, consistent with
to isolate the reactive species. The iminium ion 12, de- inoperative CH hydrogen bonding in this system.[16,17]
444
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 441– 447

Design of a Conformationally Rigid Hydrazide Organic Catalyst
UPDATES
Table 2. Effect of conformationally rigid substituents in the hydrazide-catalyzed asymmetric Diels–Alder.
Entry[a]
Catalyst
R
Yield [%][b]
exo:endo
ee [%][c] exo/endo
1
2
3
4
5
6
7
8
9
1
Ph
Ph
Ph
96
94
55
93
90
90
89
74
78
1.9:1
2.8:195/93
1.9:1
2.2:192/87
4:196/93
1.2:1
3.3:194/92
1.1:1
90/88
10
11
1
10
1
10
1
10
74/60
87/86
4-NO2C6H4
4-NO2C6H4
2-NO2C6H4
2-NO2C6H4
Me
68/72
82/80
Me
1.8:1
[a]
Reactions performed at 1M in water using 20 mol% of catalyst and TfOH.
Isolated yield.
Enantiomeric excess determined by chiral GLC.
[b]
[c]
(MS), using either electron impact (EI) or chemical ioniza-
tion (CI), was performed on a mass spectrometer with an
electron beam energy of 70 eV (for EI). Electrospray analy-
ses were run on a triple quad mass spectrometer VG QUAT-
TRO. High resolution mass spectroscopy (HR-MS) was per-
formed on a mass spectrometer with an electron beam of
70 eV, or a double focusing magnetic sector mass spectrome-
ter. GLC were performed on a gas chromatograph equipped
with a split-mode capillary injection system and a flame ion-
ization detector using CycloSil-B columns. Melting points
were measured using a Melt Temp apparatus and are uncor-
rected.
Taken together, these results suggest that manipu-
lating the conformational space available to molecules
can result in superior asymmetric organic catalysts.
This was exemplified by catalyst 10, designed with
careful consideration given to the reactive conforma-
tions available, that gave higher exo/endo ratios and
enantioselectivities in the hydrazide-catalyzed Diels–
Alder cycloadditions than our original catalyst 1. We
have also provided the first crystal structure of a key
iminium intermediate in an organocatalyzed process.
This introduces a new aspect to organocatalysis with
the introduction of a rotational barrier on the facial
directing side chain of our catalyst which could result
in the development of novel organocatalysts.
(S)-(+)-10,10-Dimethyl-3-(1-phenylethyl)-3,4-diaza-
tricyclo[5.2.1.01,5]dec-4-en-2-one
Acetic acid (0.16 mL, 3.33 mmol) was added drop wise to a
solution of (S)-(+)-ketopinic acid[18] (7.14 g, 39.2 mmol) and
(1-phenylethyl)-hydrazine (6.4 g, 47.0 mmol) in anhydrous
dichloromethane (150 mL) at room temperature. The reac-
tion mixture was stirred at that temperature until judged
complete by TLC analysis (17 h), then passed through a
short silica plug and the solvent was removed under
vacuum. The crude hydrazonocarboxylic acid was dissolved
in mesitylene (90 mL) and the resulting solution was re-
fluxed while water was removed using a Dean–Stark appara-
tus. Reflux was continued until consumption of the starting
material was complete as judged by TLC (36 h). The cooled
reaction mixture was directly purified by flash chromatogra-
phy (hexanes followed by 15% EtOAc in hexanes) to pro-
vide the desired compound as a clear oil; yield: 6.97 g
Experimental Section
General Remarks
All solvents were used as obtained from commercial suppli-
ers unless otherwise indicated. Standard inert atmosphere
techniques were employed in handling air- and moisture-
sensitive reagents. All starting materials were purchased and
were used without purification unless otherwise stated. Re-
actions were monitored by thin layer chromatography
(TLC) using commercial aluminum-backed silica gel sheets
coated with silica gel 60 F254. TLC spots were visualized
under ultraviolet light or developed by heating after treat-
ment with potassium permanganate. Room temperature cor-
responds to 228C. Excess solvents were removed under
vacuum at pressures obtained by water or air aspirators con-
nected to a rotary evaporator. Trace solvents were removed
on a vacuum pump. Product purification by flash chroma-
tography was performed with silica gel 60 (230–400 mesh).
Infrared (IR) spectra were obtained as neat films on a
sodium chloride cell. Chemical shifts are reported downfield
from tetramethylsilane (d scale) in ppm. Mass spectroscopy
(63%); IR (neat): n=2962, 1693, 1633 cmÀ1
;
1H NMR
(400 MHz, CDCl3): d=7.37–7.17 (m, 5H), 5.56–5.39 (m,
1H), 2.60–2.48 (m, 1H), 2.30–2.02 (m, 4H), 1.69–1.38 (m,
5H), 1.19 (s, 1.5H major isomer), 1.15 (s, 1.5H minor
isomer), 0.91 (s, 1.5H major isomer), 0.72 (s, 1.5H minor
isomer); 13C NMR (100 MHz, CDCl3): d (major isomer)=
174.0 (C), 173.1 (C), 141.3 (C), 128.3 (CH), 127.2 (CH),
126.8 (CH), 63.9 (CH), 51.6 (C), 49.7 (CH), 49.6 (CH), 32.0
(CH2), 26.9 (CH2), 24.9 (CH2), 19.3 (CH3), 18.8 (CH3), 18.5
Adv. Synth. Catal. 2007, 349, 441– 447
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
445

Mathieu Lemay et al.
UPDATES
(CH3); d (minor isomer)=174.0 (C), 173.2 (C), 141.8 (C),
128.2 (CH), 127.1 (CH), 126.6 (CH), 63.9 (CH), 51.7 (C),
(75 mg, 1.13 mmol) was slowly added and the resulting mix-
ture was stirred at room temperature until the reaction was
judged to be complete by TLC analysis. The reaction mix-
ture was extracted twice with ether and the combined or-
ganic extracts were washed successively with water and
brine then dried over Na2SO4. Purification by silica gel chro-
matography (5% EtOAc in hexanes) provided the desired
material as a 2.8:1mixture of exo and endo isomers (color-
less oil, 71mg, 94%). e xo ee 95%, endo ee 93%. Enantio-
meric ratios were determined using chiral GLC analysis
(Agilent/J&W CycloSil-B, 1008C hold 3 min then 28CminÀ1
gradient, flow=3.0 mLminÀ1) exo isomers tr=42.7 min,
43.8 min, endo isomers tr=43.4 min, 44.3 min. 1H NMR,
13C NMR and IR data were identical to those previously re-
ported.[6,19]
49.9 (CH), 49.2 (CH), 31.9 (CH2), 26.9 (CH2), 25.1(CH ),
2
18.9 (CH3), 18.8 (CH3), 18.5 (CH3); MS: m/z=282.2 (M+);
HR-MS: m/z=282.1718, calcd. for C18H22N2O: 282.1732.
(S)-(+)-10,10-Dimethyl-3-(R-1-phenylethyl)-3,4-diaza-
tricyclo[5.2.1.01,5]decan-2-one (10) and (S)-(+)-10,10-
Dimethyl-3-(S-1-phenylethyl)-3,4-diazatricyclo-
[5.2.1.01,5]decan-2-one (11)
To a solution of (S)-(+)-10,10-dimethyl-3-(1-phenylethyl)-
3,4-diazatricyclo[5.2.1.01,5]dec-4-en-2-one
(300 mg,
1.06 mmol) in a 2:1 mixture of acetic acid and methanol
(20 mL) was added sodium cyanoborohydride (636 mg,
10.1 mmol) in small portions over 1 h. The reaction mixture
was stirred at room temperature until TLC indicated that
the reaction was complete (21h). Excess borohydride was
Imimium Ion from (S)-(+)-10,10-Dimethyl-3-(R-1-
phenylethyl)-3,4-diazatricyclo[5.2.1.01,5]decan-2-one,
quenched by the addition of 10% HCl. The products were (E)-Cinnamaldehyde and Triflic Acid for X-Ray
extracted using CH2Cl2 and the aqueous phase was made
basic using sodium hydroxide pellets then further extracted
with CH2Cl2. The organic extracts were combined, washed
with brine and dried over Na2SO4. The solvent was removed
under vacuum and the product was purified by flash chro-
matography (30% EtOAc in hexanes) to afford the desired
compound 10 as a white solid; yield: 160 mg (53%); mp 79–
818C; [a]D: +62.18 (c 1.44, CHCl3); IR (neat): n=3249,
Analysis (12)
To a solution of (E)-cinnamaldehyde (46.0 mg, 0.352 mmol)
and (S)-(+)-10,10-dimethyl-3-(R-1-phenylethyl)-3,4-diazatri-
cyclo[5.2.1.01,5]decan-2-one 10 (100 mg, 0.352 mmol) in 19:1
CH3NO2:H2O (0.5 mL) was added CF3SO3H (31 mL,
0.352 mmol). After 4 h the solvent was removed under
vacuum to afford a yellow oil which was dissolved in a mini-
mum of THF. The solvent was then removed under vacuum
and then the sample was redissolved in THF. This cycle was
repeated several times until a pale yellow solid was ob-
tained. This material was then dissolved in a minimum
amount of THF and the mixture was allowed to stand at
À208C to afford crystals of the iminium ion that were of
suitable quality for X-ray analysis.
1
2958, 1662 cmÀ1; H NMR (500 MHz, CDCl3): d=7.38–7.35
(m, 4H), 7.26–7.22 (m, 1H), 5.50 (q, J=7.0 Hz, 1H), 3.83
(br, 1H), 3.39 (dd, J=8.3, 4.5 Hz, 1H), 2.19–2.11 (m, 1H),
2.07–2.01 (m, 1H), 1.90–1.81 (m, 2H), 1.58 (dd, J=12.9,
8.3 Hz, 1H), 1.54 (d, J=7.0 Hz, 3H), 1.28–1.23 (m, 2H),
1.22 (s, 3H), 1.07 (s, 3H); 13C NMR (125 MHz, CDCl3): d=
169.2 (C), 139.6 (C), 128.5 (CH), 127.6 (CH), 127.0 (CH),
64.9 (CH), 58.7 (C), 51.0 (C), 50.7 (CH), 46.8 (CH), 36.6
(CH2), 28.7 (CH2), 26.6 (CH2), 20.8 (CH3), 20.5 (CH3), 16.3
(CH3); MS: m/z=284.2 (M+); HR-MS: m/z=284.1888,
calcd. for C18H24N2O: 284.1889.
Supporting Information
Experimental procedures and spectral data for all new com-
pounds.
(S)-(+)-10,10-Dimethyl-3-(S-1-phenylethyl)-3,4-diazatricy-
clo[5.2.1.01,5]decan-2-one (11) was obtained as a clear oil;
yield:102 mg (34%). [a]D: À73.98 (c 1.03, CHCl3); IR
(neat): n=3248, 2959, 1659 cmÀ1
;
1H NMR (500 MHz,
Acknowledgements
CDCl3): d=7.38–7.33 (m, 2H), 7.32–7.27 (m, 2H), 7.26–7.21
(m, 1H), 5.51 (q, J=7.0 Hz, 1H), 3.45 (dd, J=8.3, 4.5 Hz,
1H), 3.32 (br, 1H), 2.15–2.06 (m, 1H), 1.89–1.78 (m, 3H),
1.70–1.64 (m, 1H), 1.57 (d, J=7.0 Hz, 3H), 1.28–1.17 (m,
2H), 1.02 (s, 3H), 0.82 (s, 3H); 13C NMR (125 MHz,
CDCl3): d=170.9 (C), 139.7 (C), 128.4 (CH), 127.6 (CH),
127.5 (CH), 66.5 (CH), 58.2 (C), 50.8 (C), 50.6 (CH), 46.9
(CH), 35.4 (CH2), 28.6 (CH2), 26.5 (CH2), 21.3 (CH3), 20.1
(CH3), 16.3 (CH3); MS: m/z=284.2 (M+); HR-MS: m/z=
284.1917, calcd. for C18H24N2O: 284.1889.
This research has been supported by NSERC, OGSST, the
Canadian Foundation for Innovation and by the University
of Ottawa. Special thanks to Tom Woo and Nick Mosey for
computational assistance and Ilia Korobkov and Patrick
Crewdson for X-ray analysis.
References
[1] a) R. Breslow, Acc. Chem. Res. 1995, 28, 146; b) Y.
Murakami, J. Kikuchi, Y. Hiseada, O. Hayashida,
Chem. Rev. 1996, 96, 721; c) A. J. Kirby, Angew. Chem.
Int. Ed. Engl. 1996, 35, 707; d) N. Gathergood, Austral-
ian J. Chem. 2002, 55, 615; e) H. Grçger, J. Wilken,
Angew. Chem. Int. Ed. 2001, 40, 529.
[2] a) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001,
40, 3726; b) B. List, Synlett 2001, 1675; c) P. I. Dalko, L.
Moisan, Angew. Chem. Int. Ed. 2004, 43, 5138; d) K. N.
(1R,2R,3R,4S)-3-Phenylbicyclo[2.2.1]hept-5-ene-2-
carboxaldehyde and (1S,2S,3S,4R)-3-phenylbicyclo-
[2.2.1]hept-5-ene-2-carboxaldehyde (Table 2, entry 2)
A
To a suspension of (E)-cinnamaldehyde (50 mg, 0.378 mmol)
in distilled water (0.4 mL) was added (S)-(+)-10,10-dimeth-
yl-3-(R-1-phenylethyl)-3,4-diazatricyclo[5.2.1.01,5]decan-2-
one 10 (21.5 mg, 0.076 mmol) followed by CF3SO3H (6.7 mL,
0.07 mmol). After stirring for 1to 2 min, cyclopentadiene
446
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 441– 447

Design of a Conformationally Rigid Hydrazide Organic Catalyst
UPDATES
Houk, B. List, Acc. Chem. Res. 2004, 37, 487; e) M. L.
Clarke, Lett. Org. Chem. 2004, 1, 292; f) W. Notz, R.
Tanaka, C. F. Barbas, III, Acc. Chem. Res. 2004, 37,
580; g) J. Seayad, B. List, Org. & Biomol. Chem. 2005,
3, 719; h) A. Berkessel, H. Grçger, Asymmetric Orga-
nocatalysis, Wiley VCH, Weinheim, 2005.
[10] Gaussian 98 (Revision A.9). PM3: a) J. J. P. Stewart, J.
Comp. Chem. 1989, 10, 209; b) J. J. P. Stewart, J. Comp.
Chem. 1989, 10, 221.
[11] Allylic-type strain is also possible between the benzyl
side-chain and the iminium moiety but was apparently
less significant.
[12] I. Fleming, Fronteir Orbitals and Organic Chemical Re-
actions. Wiley-Interscience, Chichester, 1976.
[13] CCDC 610170 and 610171 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data
request/cif, or by emailing data request@ccdc.cam.
ac.uk, or by contacting The Cambridge Crystallograph-
ic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; fax: (+44)-1223–336033.
[14] Recently the structure of a hydrogen-bonded inter-
mediate was disclosed: R. I. Storer, D. E. Carrera, Y.
Ni, D. W. C. MacMillan, J. Am. Chem. Soc. 2006, 128,
84.
[15] V. S. Bryantsev, B. P. Hay, J. Am. Chem. Soc. 2005, 127,
8282.
[16] Our previous results show that the presence of non-co-
ordinating counterions such as triflate, perchlorate and
tetrafuloroborate is important in these reactions, see
ref.[7]
[17] Significant couterion effects have been noted in other
organocatalytic cycloadditions, see: a) J. L. Cavill, J.-U
Peters, N. C. O. Tomkinson, J. Chem. Soc., Chem.
Commun. 2003, 728; b) J. L. Cavill, R. L. Elliot, G.
Evans, I. L. Jones, J. A. Platts, A. M. Ruda, N. C. O.
Tomkinson, Tetrahedron 2006, 62, 410; see also ref.[9]
[18] P. P. Bartlett, L. H. Knox, Organic Syntheses, Coll. Vol.
5, p. 689.
[3] a) B. List, Tetrahedron 2002, 58, 5573; b) M. Movassa-
ghi, E. N. Jacobsen, Science 2002, 298, 1904.
[4] For examples, see: a) M. M. Vasbinder, E. R. Jarvo, S. J.
Miller, Angew. Chem. Int. Ed. 2001, 40, 2824, and refer-
ences cited therein; b) P. Vachal, E. N. Jacobsen, J. Am.
Chem. Soc. 2002, 124, 10012, and references cited
therein.
[5] L. Pignataro, M. Benaglia, R. Annunziata, M. Cinquini,
F. Cozzi, J. Org. Chem. 2006, 71, 1458.
[6] M. Lemay, W. W. Ogilvie, Org. Lett. 2005, 7, 4141.
[7] M. Lemay, W. W. Ogilvie, J. Org. Chem. 2006, 71, 4663.
[8] a) K. A. Ahrendt, C. J. Borths, D. W. C. MacMillan, J.
Am. Chem. Soc. 2000, 122, 4243; b) A. B. Northrup,
D. W. C. MacMillan, J. Am. Chem. Soc. 2002, 124,
2458; c) R. M. Wilson, W. S. Jen, D. W. C. MacMillan, J.
Am. Chem. Soc. 2005, 127, 11616; d) K. Kim, L. S.
Hoon; D.-W. Lee, D.-H. Ko, D.-C Ha, Tetrahedron
Lett. 2005, 46, 5991; e) K. Ishihara, K. Nakano, J. Am.
Chem. Soc. 2005, 127, 10504; f) S. A. Selkälä, A. Sami,
A. M. P Koskinen, Eur. J. Org. Chem. 2005, 1 620;
g) D. C. Braddock, I. D. MacGilp, B. G. Perry, Synlett
2003, 1121; h) S. A. Selkälä, J. Tois, P. M. Pihko,
A. M. P. Koskinen, Adv. Synth. Catal. 2002, 344, 941;
i) R. Gordillo, K. N. Houk, J. Am. Chem. Soc. 2006,
128, 3543.
[9] a) C. Allemann, R. Gordillo, F. R. Clemente, P. H.-Y.
Cheong, K. N. Houk, Acc. Chem. Res. 2004, 37, 558;
b) R. Gordillo, K. N. Houk, J. Am. Chem. Soc. 2006,
128, 3543.
[19] H. Fujioka, N. Kotoku, T. Fujita, R. Inoguchi, K.
Murai, Y. Nagatomi, Y. Sawama, Y. Kita Chirality
2003, 15, 60.
Adv. Synth. Catal. 2007, 349, 441– 447
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
447