5-(Pyrrolidine-2-yl)tetrazole: Rationale for the increased reactivity of the tetrazole analogue of proline in organocatalyzed aldol reactions

Article abstract of DOI:10.1002/ejoc.200500470

5-[(2S)-Pyrrolidine-2-yl]-1H-tetrazole (1), i.e. the tetrazolic acid analogue of proline, has been found to be significant more reactive than L-proline (2) in various organocatalyzed reactions. In the organocatalyzed direct asymmetric aldol reaction, acetone was reacted with aromatic and aliphatic aldehydes to afford the resulting β-hydroxy ketones in good yields and moderate to high enantiomeric excesses. The increased reactivity of 1, as compared to 2, has been rationalized through a combined computational and NMR spectroscopic study. It was found that catalyst 2 was almost completely engaged in oxazolidinone formation with the aldehyde whereas 1 did not take part in such parasitic equilibrium. This finding, together with the improved solubility of the tetrazole analogue, is proposed to account for the observed reactivity. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500470

FULL PAPER
5-(Pyrrolidine-2-yl)tetrazole: Rationale for the Increased Reactivity of the
Tetrazole Analogue of Proline in Organocatalyzed Aldol Reactions
Antti Hartikka[a] and Per I. Arvidsson*[a]
Keywords: Organocatalysis / Tetrazole / Aldol reactions / Asymmetric catalysis / Computational chemistry
5-[(2S)-Pyrrolidine-2-yl]-1H-tetrazole (1), i.e. the tetrazolic
acid analogue of proline, has been found to be significant
more reactive than L-proline (2) in various organocatalyzed
reactions. In the organocatalyzed direct asymmetric aldol re-
action, acetone was reacted with aromatic and aliphatic alde-
hydes to afford the resulting β-hydroxy ketones in good
yields and moderate to high enantiomeric excesses. The in-
creased reactivity of 1, as compared to 2, has been rational-
ized through a combined computational and NMR spectro-
scopic study. It was found that catalyst 2 was almost com-
pletely engaged in oxazolidinone formation with the alde-
hyde whereas 1 did not take part in such parasitic equilib-
rium. This finding, together with the improved solubility of
the tetrazole analogue, is proposed to account for the ob-
served reactivity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
reactivity and low solubility of the catalyst. Second-genera-
tion catalysts, in which the carboxylic acid function of pro-
line is replaced by known bio-isosteres such as tetrazolic
acids or N-sulfonylamides[11] have therefore recently
emerged, and have been proven to show dramatically im-
proved reactivity and/or selectivity for many organocata-
lyzed reactions. Other novel organocatalysts, based on tri-
peptides[12] have also been developed.
After the initial discovery by Ley,[13] Yamamoto,[14] and
ourselves,[15] the use of the catalyst 5-[(2S)-pyrrolidine-2-yl]-
1H-tetrazole (1), i.e. the tetrazolic acid analogue of proline
2, has expanded to organocatalyzed variants of enantiose-
lective aldol condensations,[16] O-nitroso aldol/Michael re-
action,[17] and addition to nitro olefins.[18] Lately, Barbas
and co-workers employed tetrazole 1 as a highly active cata-
lyst for the creation of a quaternary stereocenter in a total
synthesis of LFA-1 antagonist BIRT-377.[19]
The direct asymmetric aldol condensation between un-
modified ketones and aldehydes relies on activation of the
ketone partner through formation of the corresponding en-
amine as an intermediate through condensation with the
secondary amine function of the catalyst, Scheme 1. The
reactive enamine then attacks the aldehyde via an ordered
Zimmerman–Traxler like transition state. A high concentra-
tion of acetone is used to suppress formation of by-pro-
ducts and in order to drive the reaction equilibrium towards
product.
Introduction
The aldol reaction is one of the most important carbon–
carbon bond-forming reactions; therefore, the widespread
interest in developing asymmetric variants of this reaction
is not surprising. The asymmetric aldol reactions reported
today rely on: the use of chiral auxiliaries, catalysts that
facilitate reaction between preformed enolates and alde-
hydes, and catalysts capable of inducing reaction between
unmodified ketones and aldehydes.[1,2]
Catalysts facilitating the direct asymmetric addition reac-
tion between unmodified ketones and aldehydes has been
developed by Shibasaki and Trost using heterobimetallic
catalysts,[3–4] whereas Lerner and others have used more
naturally inspired catalytic systems consisting of aldolase
enzymes and catalytic antibodies.[5–6] An organocatalytic
approach utilizing l-proline as catalyst for an intramolecu-
lar aldol cyclization, also termed the Hajos–Parrish–Eder–
Sauer–Wichert reaction, was reported some thirty years
ago.[7] Recently List et al. demonstrated that l-proline also
could mediate the intermolecular aldol reaction using un-
modified ketones and aldehydes.[8] This report has sparked
a tremendous renewed interest in the area of asymmetric
catalysis by small organic molecules, e.g. organocatalysis,
with both proline[9] and other molecular entities.[10]
Although proline is an ideal catalyst in terms of price
and availability, often-encountered drawbacks relates to low
In our initial report on catalyst 1 we reasoned that part
of the increased reactivity was due to a greater charge-stabi-
lization in the aldol reaction transition state by the tet-
razolic acid function, in comparison to the carboxylic acid
in 2. However, in this full account of our studies of 1 we
find that the main reason for the increased reactivity of 1
[a] Department of Chemistry, Organic Chemistry, Uppsala Univer-
sity,
5124 Uppsala, Sweden
Fax: +46-18-4713818
E-mail: Per.Arvidsson@kemi.uu.se
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2005, 4287–4295
DOI: 10.1002/ejoc.200500470
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4287

A. Hartikka, P. I. Arvidsson
FULL PAPER
effect upon substitution of the carboxylic acid to the tet-
razolic acid in terms of reactivity and selectivity. Initially,
the reaction between acetone and the three aldol acceptors
4-nitrobenzaldehyde (7), 2,2-dimethylpropionaldehyde (8),
and 4-methoxybenzaldehyde (9) was evaluated. A large ex-
cess of acetone (20% of the solvent volume) was used in
order to drive the equilibrium towards products. The reac-
tion was followed directly by performing the reaction in an
NMR tube using [D6]DMSO as solvent and suppression of
the acetone signal by the WET-pulse sequence.[21]
The results presented in Figure 1 clearly show that 1 is
significantly more reactive than 2, especially when the less
reactive substrates like 4-methoxybenzaldehyde and 2,2-di-
methylpropionaldehyde is used as substrates.
Scheme 1.
over 2 in the organocatalyzed aldol reaction, and most
likely also in other organocatalyzed reactions, is mainly at-
tributed to the lack of parasitic bicyclo-oxazolidinone for-
mation between the aldehyde and catalyst 1.
Results and Discussion
Synthesis
The new organocatalyst 1 was synthesized from commer-
cially available l-proline (2) according to Scheme 2.
The synthesis commenced with Cbz protection of l-pro-
line[20a] 2 to yield 3, which was subsequently transformed
to amide 4, utilizing in situ activation of the carboxylic ac-
id.[20b] Subsequent dehydration furnished the corresponding
nitrile 5 in high yield,[20c–d] which was further transformed
into the protected tetrazole 6 utilizing the “click chemistry”
protocol developed in the Sharpless laboratory.[20e–20f]
The target compound 1, which can be represented by the
Figure 1. Graph showing the conversion of starting material into
product as a function of time during the direct organocatalyzed
asymmetric aldol reaction between acetone and aldehydes 4-ni-
trobenzaldehyde (7), 2,2-dimethylpropionaldehyde (8), and 4-meth-
two tautomers 1-1H and 1-2H, was obtained after catalytic oxybenzaldehyde (9) using catalyst 1 (solid markers) and catalyst 2
hydrogenation and purification by a solid-phase catch and
(empty markers).
release procedure. This highly efficient synthesis furnished
It should also be noted that proline was far more active
the desired product in 75% overall yield, without any de-
in the archetypal reaction between acetone and 4-nitrobenz-
tectable racemization.[20g]
aldehyde than previously reported, giving the aldol product
in 76% isolated yield after only thirty minutes.
Having established the higher reactivity of 1, as com-
Asymmetric Aldol Reaction
pared to 2, we next evaluated the potential of 1 as a catalyst
The new tetrazole catalyst was assessed in the direct for the direct asymmetric aldol reaction between acetone
asymmetric aldol condensation in order to investigate the and a selection of aliphatic and aromatic aldehydes. Ini-
Scheme 2. Synthesis of 1. (i) Cbz-Cl, NaOH, 5°C; (ii) (Boc)2O, NH4HCO3, CH3CN, cat. pyridine; (iii) Cyanuric chloride, DMF;
(iv) NaN3, ZnBr2, water/2-propanol; (v) H2O, AcOH, H2, Pd/C.
4288
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4287–4295

5-(Pyrrolidine-2-yl)tetrazole
FULL PAPER
tially, all reactions were run at small scale and monitored
by NMR as described above, to find the optimal reaction
time for each substrate (see the supporting information for
graphs of conversion vs. time). Next, the reactions were run
on larger scale to afford the isolated products 7–14 reported
in Table 1.
Table 1. Direct asymmetric aldol reaction between acetone and the
listed aldehydes catalyzed by 1 in DMSO at room temperature.
Figure 2. Graph showing the conversion of 2,2-dimethylpropional-
dehyde (8) into the product (R)-4-hydroxy-5,5-dimethylhexane-2-
one as a function of time during the organocatalyzed direct asym-
metric aldol reaction with acetone using catalyst 1 (20 mol%, and
5 mol%) and 2 (20 mol%).
As reported in our initial study,[15] the solubility of cata-
lyst 1 allows it to be used in other solvents than DMSO,
with maintained, or slightly lowered, performance. Diox-
ane, dimethylformamide, and tetrahydrofuran were found
to be suitable solvents for the direct asymmetric aldol reac-
tion with catalyst 1. Especially dimethylformamide was
interesting, as this solvent allowed the reaction temperature
to be decreased with only a small reduction in conversion,
but a substantial increase in enantioselectivity (Table 2).
Table 2. Selected solvents from previous solvent study.
Entry Solvent
T[a]
[°C]
Conv.[b] Yield[c] ee[d]
ee[e]
[%]
[%]
[%]
[%]
1
2
3
4
5
6
DMF
DMF
DMF
dioxane
dioxane
DMF/
H2O[f]
DMF/
H2O[f]
THF
23
5
–50
23
5
99
93
80
77
87
78
89
70
80
82
66
67
76
69
81
86
64
67
76
96
99[g]
99
84
99
23
7
5
75
73
77
81
[a] Isolated yield after column chromatography. [b] Enantiomeric
excess determined by chiral HPLC analysis (Chiralpak AS and Chi-
ralpak AS-H). [c] Enantiomeric excess determined by chiral HPLC
analysis (Chiralpak AD). [d] Catalyst loading 5 mol% and reaction
time 40 h.
8
9
10
23
5
–50
99
88
77
76
51
62
72
53
65
72
THF
THF
95
99[g]
[a] Temperature was held constant with aid of a thermostat. [b]
Reaction time was 4 hours and conversions were determined on
crude products by means of HPLC analysis. [c] Yields after column
chromatography. [d] Enantiomeric excess was determined by chiral
HPLC analysis on crude products. [e] Enantiomeric excess was de-
termined on aldol adducts purified by column chromatography. [f]
Mixture of (9:1) (DMF/water) was employed as solvent. [g] Reac-
tion time was eight hours.
As seen from the optimized reaction times in Table 1,
aliphatic aldehydes as a substance class are less reactive
than the aromatic aldehydes investigated. Nevertheless, the
high catalytic activity of the tetrazole catalyst allows all ali-
phatic aldehydes to be transformed to chiral β-hydroxy
ketones with high enantioselectivity and fair yields within
12 hours.
The increased reactivity if 1 suggests that it should be
Earlier reports have stated that the proline-catalyzed
possible to lower the catalyst loading from the 20% typi- asymmetric aldol reaction was highly sensitive towards
cally used when proline is employed as catalyst. Indeed, as water.[22a–22b] The results at hand indicate that catalyst 1
seen in Table 1 (entry 2) and in Figure 2, the catalyst load- (Table 2, entry 7–8) tolerates the presence of 10% of water
ing could be lowered by 300%, and still provides a turnover without affecting the enantioselectivity, conversions, or iso-
which match the reactivity of 2 at higher loading.
lated yield.
Eur. J. Org. Chem. 2005, 4287–4295
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4289

A. Hartikka, P. I. Arvidsson
FULL PAPER
Figure 3. Geometry-optimized structures of the initial state and transition state of the proline (IS2A and TS2A) and tetrazole-catalyzed
(IS1A and TS1A) asymmetric aldol reaction between acetone and 2,2-dimethylpropionaldehyde. Geometries are optimized at B3LYP/6-
31G(d,p) level of theory and ZPE corrected. Energies in solution refers to single point B3LYP/6-311+G(d,p) calculations in DMSO using
a self-consistent reaction field method and are ZPE corrected.
Theoretical Studies
been shown to play a vital role on previous theoretical stud-
ies on this reaction, we next performed single point B3LYP/
6-311+G(d,p) calculations in DMSO using a self-consistent
reaction field method.[25] Again, the activation energy for
the proline mediated reaction was found to be lower than
the aldol reaction catalyzed by the tetrazole catalyst. Thus,
none of the calculations done on the C–C bond formation
step rationalize the much higher reactivity of the tetrazole
catalyst observed experimentally.
We therefore next examined the enamine formation step,
which has been suggested to have comparable activation en-
ergy as the carbon–carbon bond formation (vide supra), to
see if we could detect a larger difference for the two cata-
lysts in this step.
As can be seen in Figure 4, the activation energy for this
step is clearly different for the two catalysts. In the gas-
phase, catalyst 2 needs 7.2 kcalmol–1 for the enamin forma-
tion, while the corresponding energy for catalyst 1 is only
2.1 kcalmol–1. However, upon including solvation effects in
the calculations, both catalysts experience a dramatic in-
crease in activation energy, due to the stabilizing effect of
the solvent on the charged initial states for these reactions.
Consequently, according to these calculations, the enamine
formation now becomes the rate-determining step instead
of the carbon–carbon bond formation for both these cata-
lysts. A similar activation energy for the enamine formation
and the aldol reaction step was also noted in Houk’s most
recent calculations on the intramolecular reaction.[23b]
In attempt to find a lower energy route for the enamine
In order to provide a plausible explanation for the in-
creased reactivity of the tetrazole catalyst, as compared to
proline, we decided to study the reaction between 2,2-di-
methylpropionaldehyde and acetone computationally. Se-
veral recent studies have addressed both the intramolecu-
lar[23a] as well as the intermolecular[23b] proline-catalyzed
asymmetric aldol reaction by computational means. Houk
et al. first rationalized the observed stereoselectvity for the
intermolecular reaction,[24a] while Boyd[24b] later presented
a detailed study on most parts of the possible reaction path,
and suggested that the rate-determining step in the gas
phase is the initial condensation between proline and the
ketone, while calculations incorporating solvation effects
suggested the rate-determining step to be the carbon–car-
bon bond forming step, as previously proposed by List et
al.[24c] An identical activation energy for the enamine for-
mation and the carbon–carbon bond formation was re-
cently reported by Houk et al. in new calculations[24d] on
the intramolecular reaction.
Based on the many detailed theoretical studies address-
ing the stereoselectivity of the proline-catalyzed reactions,
we restricted ourselves to a comparison between the proline
and the tetrazole catalyst in terms of the proposed rate-
determining steps. In our case, we did not limit ourselves
to study a model system, but instead performed all calcula-
tion on the full system involving the condensation of ace-
tone with 2,2-dimethylpropionaldehyde. Figure 3 shows the
B3LYP/6-31G(d,p)-optimized structures of the initial states formation, we also investigated a water-mediated process.
and the transition states for the previously established low- One molecule of water is liberated upon forming the imin-
est energy route leading to the product with experimentally ium ion from the catalyst and acetone; this water molecule
verified stereochemistry.
is suitably located for assisting the transformation of then
Surprisingly, the initial calculation in gas-phase sug- imine to the enamine. However, upon investigating the bar-
gested that the proline-catalyzed reaction has a lower acti- rier for this, previously neglected, pathway an even higher
vation energy than the tetrazole catalyst. As solvation has activation enthalphy was found. Figure 5 shows the water-
4290
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4287–4295

5-(Pyrrolidine-2-yl)tetrazole
FULL PAPER
Figure 4. Geometry-optimized structures of the initial state and transition state of the proline (IS2B and TS2B) and tetrazole (IS1B and
TS1B) mediated enamine formation. Geometries are optimized at B3LYP/6-31G(d,p) level of theory and ZPE corrected. Energies in
solution refers to single point B3LYP/6-311+G(d,p) calculations in DMSO using a self-consistent reaction field method and are ZPE
corrected.
Figure 5. Geometry-optimized structures of the initial state and transition state of the proline- (IS2C and TS2C) and tetrazole-mediated
(IS1C and TS1C) enamine formation occurring through the active participation of one water molecule. Geometries are optimized at
B3LYP/6-31G(d,p) level of theory and ZPE corrected. Energies in solution refers to single point B3LYP/6-311+G(d,p) calculations in
DMSO using a self-consistent reaction field method and are ZPE corrected.
mediated enamine formation, shown to be substantially
higher in energy, as compared to the process not mediated
by water .
No matter which step is actually rate limiting in the real
situation, none of our computational studies showed a
lower activation enthalphy in solution for the tetrazole cata-
List et al. have established that such oxazolidinone for-
lyst, as compared to proline. Thus, after the computational
mation leads to a parasitic consumption of the catalyst for
study was completed it was clear that we needed to find an
the aldol reaction in DMSO, while Blackmond et al.
alternative explanation for the increased activity of catalyst
showed that bicyclic oxazolidinone formation in the pro-
1 in the asymmetric aldol reaction found experimentally.
line-catalyzed α-aminoxylation and α-amination reactions
may actually make the catalyst more active by increasing
the solubility of proline or itself participate as a catalyst in
NMR Spectroscopic Studies
the reaction.[27a–c]
In order to find additional reasons for the increased reac-
To us, it appeared reasonable that the carboxylic acid in
tivity of the tetrazole catalyst, we next turned to NMR proline and the tetrazolic acid in 1 should have different
spectroscopic studies. Several reports have highlighted the reactivity towards aldehydes and ketones. To establish this,
importance of bicyclic oxazolidinones of type 15 and 16 we performed a reaction between 2,2-dimethylpropionalde-
formed between the proline and the aldehyde or hyde and catalysts 1 and 2, respectively, in the absence of
ketone.[26a–26b]
acetone. The bicyclic oxazolidinone adduct thus expected
Eur. J. Org. Chem. 2005, 4287–4295
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4291

A. Hartikka, P. I. Arvidsson
FULL PAPER
Figure 6. Expansion of 1H NMR spectra of a mixture of 2,2-dimethylpropionaldehyde and 2 (a) or 1 (b) in [D6]DMSO. The spectra
show almost quantitative formation of bicyclic oxazolidinone with 2 while 1 does not take part in such equilibrium. Spectra recorded in
[D6]DMSO at Ccat. = 0.196 m, Caldehyde = 0.196 m.
i.e. 15, has been described earlier.[26b,28] An NMR spectro-
Experimental Section
scopic investigation showed that whereas 2 almost quantita-
Chemicals and solvents were either purchased puris p.A. from com-
tively existed as the corresponding bicyclic oxazolidinone
mercial suppliers or purified by standard techniques. For thin layer
(Figure 6, a) the corresponding tetrazole analogue 1 existed
chromatography (TLC), precoated 0.25 mm silica plates (Mach-
1
erey–Nagel 60 Alugram® Sil G/UV254) were used and spots were
visualized either with UV light, ethanolic phosphomolybdic acid
followed by heating, by 0.5% 2,4-dinitrophenylhydrazine in 2 m
HCl followed by heating or by a solution composed of p-anisal-
dehyde (23 mL), concentrated H2SO4 (35 mL), acetic acid (10 mL)
and 900 mL ethanol followed by heating. Column chromatography
was performed on silica gel (Matrex™ 60A, 37–70 μm). Macropo-
rous polystyrene-sulfonic acid (MP-TsOH) was purchased from Ar-
gonaut. 1H NMR 500 MHz spectra was recorded on a Varian
Unity 500 MHz and 13C NMR 100 MHz spectra were recorded on
a Varian Unity 400 MHz spectrometer at ambient temperature
using deuturated chloroform, water or dimethylsulfoxide as sol-
vent. Chemical shifts (δ) in ppm are reported using residual chloro-
form, water or dimethylsulfoxide as internal reference (1H δ = 7.26,
13C δ = 77.0 ppm), (1H δ = 4.2 ppm) or (1H 2.49, 13C δ = 77.0 ppm)
and coupling constants (J) in Hz. High pressure liquid chromatog-
raphy (HPLC) was done on a Gilson system consisting of a Gilson
322 pump, Gilson 233 XL autosampler, Gilson UV/Vis 152 detec-
tor or an evaporative light scattering detector (Sedere, Sedex75).
completely free i.e. no cyclic structure was identified by H
NMR spectroscopy, Figure 6, b. Formation of the oxazolid-
inone causes the tert-butyl group protons (singlet) to be
shifted to higher field, as seen in Figure 6.
The same experiment was performed using a large excess
of acetone. Although several species, including what ap-
pears to be the product of acetone self condensation, were
seen, none of them could be assigned to the tricyclic tetra-
zole analogue of oxazolidinone 16 previously described to
form between acetone and proline.[26a]
Conclusions
We have demonstrated that replacement of the carboxy
group in l-proline by the corresponding tetrazolic acid
leads to a new organocatalyst. This catalyst has been widely
employed in the literature and is known to have better solu-
bility than proline in most solvents. The tetrazole-based cat-
alyst 1 has also been shown to be more reactive and some-
times yield higher stereoselectivities, as compared to pro-
line, when employed as catalyst in organocatalyzed reac-
tions. In this account we have tried to rationalize the in-
creased reactivity of 1 in the direct asymmetric aldol reac-
tion between acetone and various aldehydes. A computa-
tional investigation of the transition states involved failed
to provide any evidence for the underlying reason for the
increased activity. However, an NMR spectroscopic investi-
gation of a mixture of the catalyst and the aldehyde showed
that proline easily engage in parasitic bicyclic oxazolidinone
formation, while catalyst 1 does not. Consequently, more
catalyst is available for forming the enamine intermediate in
the aldol reaction in the case of catalyst 1 than when proline
is used. We suggest that his is the main reason for the in-
creased reactivity of 1 in DMSO solution, while factors re-
lated to solubility may also contribute in other solvent sys-
tems.
Analytical HPLC runs were done in the straight phase mode Chi-
ralpak AS, Chiralpak AS-H and Chiralpak AD (5μ, 4.6×250 mm)
with hexane/2-propanol as mobile phase (isocratic 70:30, isocratic
90:10, isocratic 97:3, 1.0 mL/ min and 0.7 mL/ min) for enantio-
selectivity determination. Reverse phase HPLC was done using a
Kromasil C18 (5 μ, 4.0×150 mm) column (for purity determi-
nation) with acetonitrile/water (both containing 0.1% TFA) as mo-
bile phase (Gradient: 5–50% acetonitrile, flow 1.5 mL/ min) and a
Chirobiotic T (5 μ, 4.6×250 mm) column (for enantiomeric excess
determination) of the amino acid derivative 1 with water as mobile
phase (isocratic 100% water, 2.5 mL/ min).
Gas chromatography coupled with mass spectra detection was done
with a Finnigan MAT GCQ PLUS system equipped with an
AS2000 auto injector from CE, and a n.v. rescom SE54 (30 m×250
μm) column using nitrogen as carrier gas and electron impact ion-
ization (EI, 70 eV). GC program: 100°C, hold 4 min then 100–
250°C (20°C/min). Mass spectra recorded by means of direct in-
fusion technique were performed on a Finnigan MAT GCQ PLUS
system using electron impact ionization (EI, 70 eV) and chemical
ionization using methane gas. Infrared spectra were recorded on a
Perkin–Elmer 1760 FT-IR spectrometer. Melting point determi-
nation was done with a melting point apparatus, SMP3 from Stuart
4292
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4287–4295

5-(Pyrrolidine-2-yl)tetrazole
FULL PAPER
Scientific. A thermostat was used to maintain a constant tempera-
ture in the reaction (25°C and 0°C) supplied by Grant. For the
run at –50°C a chloroform/liquid nitrogen bath was employed.
data.[20e] Direct infusion MS (CI) m/z (rel. intensity): 274.1 ([M +
H]+,70), 230.3 (74), 160.3 (28), 91.5 (100), 70.5 (60).
5-[(2S)-Pyrrolidine-2-yl]-1H-tetrazole (1): 5-[(2S)-1-(Benzyloxycar-
bonyl)pyrrolidin-2-yl]tetrazole (6) (2.3 g; 8.7 mmol) was dissolved
in 100 mL (9:1) (acetic acid/water). To this homogeneous solution
was added (0.23 g; 10wt.-%) palladium on carbon. The flask was
placed under a hydrogen atmosphere and stirred for 72 h. The solu-
tion was filtered and concentrated under reduced pressure to give
a colourless oil 1.3 g. The oil was dissolved in 20 mL methanol and
10 g of a macroporous polystyrene-sulfonic acid (MP-TsOH) was
added to the homogeneous solution. The solution was stirred for
one hour. The resin was washed with three times 40 mL methanol
and then the compound was released with 8×30 mL of a solution
of sat. ammonia in methanol. The solution was concentrated under
reduced pressure to give the title compound as an off-white solid;
yield 1.1 g (95%); m.p. 269–271°C. [α]rD.t. = –1.1 (c = 1, CH3OH).
N-(Benzyloxycarbonyl)-L-proline (3): To a cold solution (5°C) of
(S)-proline 2 (15 g; 0.13 mol) in 60 mL of 2 m sodium hydroxide
was added under vigorous stirring alternatingly benzyl chloro-
formate (90 g; 0.17 mol) and 47 mL of a 4 m sodium hydroxide
solution. The mixture was stirred for an additional two hours at
5°C after which the mixture was washed with 2×40 mL of diethyl
ether. The aqueous layer was acidified to pH 1, saturated with so-
dium chloride and then extracted with ethyl acetate 3×50 mL. The
combined extracts were dried with MgSO4, filtered, and concen-
trated under reduced pressure to give (29.2 g; 90%) of a pale yellow
oil which was considered sufficiently pure for further use. 1H NMR
and 13C NMR were identical to earlier reports.[29] Direct infusion
MS (CI) m/z (rel. intensity): 250.2 ([M + H]+, 54), 206.3 (60), 160.3
(92), 114.2 (18), 91.4 (96), 70.5 (100).
IR (KBr): ν = 3380 cm–1 (br., m), 2930 (s), 2535 (br., s), 1980 (br.,
˜
1
m). H NMR (500 MHz; [D6]DMSO): δ = 9.1 (br. s, 1 H), 4.8 (m,
N-(Benzyloxycarbonyl)-L-prolinamide (4): To a round-bottomed
1 H), 2.5–2.4 (m, 1 H), 3.4–3.2 (m, 3 H), 2.4–2.2 (m, 1 H), 2.15–
1.9 (m, 3 H) ppm. 13C NMR (100 MHz; [D6]DMSO): δ = 158.9,
54.6, 45.8, 29.7, 23.6 ppm. ESI-MS, m/z (rel. intensity): 140.0
(MH+, 100); HPLC-ELSD on both reversed phase (Kromasil C18)
and a chiral column (Chirobiotic T) showed only one peak which
confirmed the purity and the stereochemical integrity of the ob-
tained material.
flask was added N-(benzyloxycarbonyl)-l-proline (3) (28 g; 0.11
mol), di-tert-butyl pyrocarbonate (37 g; 0.17 mol), ammonium hy-
drogen carbonate (13 g; 0.166 mol) and acetonitrile 500 mL. The
reaction flask was flushed with nitrogen and sealed. Pyridine (6 ml;
80 mmol) was slowly added to the mixture and the resulting mix-
ture was left stirring 68 hours. To the mixture was added 50 mL
water and the volume was reduced under vacuum to approximately
50 mL. The mixture was extracted with dichloromethane (3×50
mL) and the combined extracts were washed with saturated
NaHCO3 (3×50 mL), 0.2 m HCl (3×50 mL) and brine (50 mL).
The solution was dried with MgSO4, filtered, and concentrated un-
der reduced pressure to give the title compound as yellow oil
(26.8 g; 96%). The 1H NMR and 13C NMR was identical to the
previously reported data.[30] Direct infusion MS (CI) m/z (rel. in-
tensity): 249.0 ([M + H]+,10), 204.0 (50), 160.3 (90), 91.4 (100),
65.6 (18).
General Procedure (GP1) for Direct Asymmetric Aldol Reaction: To
a solution of 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole in solvent/ace-
tone (4:1 v/v, 2.72 m) was added the aldehyde. The solution was
stirred for the required time and then quenched with saturated am-
monium chloride and extracted with ethyl acetate. The organic
layer was dried with sodium sulfate, filtered, and concentrated to
give pure aldol products after column chromatography.
4-Hydroxy-4-(4Ј-nitrophenyl)butan-2-one (7): Synthesized according
to GP1. 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole (0.02 mmol),
DMSO/acetone (1 mL), and 4-nitrobenzaldehyde (15.1 mg, 0.1
mmol). Column chromatography (pentane/ethyl acetate, 5:4); yield
17.2 mg (82%); Rf = 0.43; direct infusion MS (EI) m/z (rel. inten-
N-(Benzyloxycarbonyl)-L-prolinenitrile (5): To a 500-mL round-bot-
tomed flask was added N-(benzyloxycarbonyl)-l-prolinamide (4)
(25.6 g; 0.10 mol) and dimethylformamide 330 mL. The flask was
capped with a drying tube (CaCl2). The solution was chilled in an
ice bath and cyanuric chloride (14 g; 74.7 mmol) was added in one
shot where after the solution was allowed to slowly reach room
temperature and stirring was continued for 79 hours. The reaction
was quenched with 650 mL water and the solution was extracted
with ethyl acetate (2×500 mL). The organic phase was washed with
water (4×250 mL), dried with magnesium sulfate, filtered, and con-
centrated under reduced pressure to give a pale yellow oil (22.8 g;
96%) which was considered sufficiently pure for further use. The
1H NMR and 13C NMR was identical to the previously reported
data.[20g] Direct infusion MS (CI) m/z (rel. intensity): 231.0 ([M +
H]+, 8), 204.0 (100), 160.2 (50), 91.4 (50), 70.5 (100).
1
sity): 209.3 (M+,12), 192.3 (18), 174.3 (100), 144.3 (60). H NMR
and 13C NMR are identical to earlier published results.[31] Enantio-
meric excess determined by HPLC (Daicel Chiralpak AS-H,
iPrOH/hexane, 30:70), UV 254 nm, flow rate 1.0 mL/min. (R) iso-
mer, tr = 11.2 min and (S) isomer, tr = 14.3 min.
4-Hydroxy-5,5-dimethylhexane-2-one (8): Synthesized according to
GP1. 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole (0.12 mmol), DMSO/
acetone (6 mL), 2,2-dimethylpropionaldehyde (51.6 mg, 0.6 mmol),
the mixture was stirred for 12 h. Column chromatography (pen-
tane/ethyl acetate, 4:1); yield 59.5 mg (69%) of a colorless oil; Rf =
0.31; direct infusion MS (CI) m/z (rel. intensity): 145.2 (M+1, 100),
127.2 (80), 109.2 (78), 87.1 (10). GC-MS analysis (GC Column:
n.v. rescom SE54), tR = 6.85 min (CI) m/z (rel. intensity): 145.2
(M+1, 100), 127.2 (80), 109.2 (78), 87 (10). 1H NMR spectroscopic
data were identical to earlier published results.[31] 13C NMR
(100 MHz, CDCl3): δ = 26.6 (3 C), 34.1 (1 C), 45.1 (1 C), 74,8
(1 C), 210 (1 C) ppm. Enantiomeric excess was determined by
HPLC (Daicel Chiralpak AD, iPrOH/hexane, 3:97), UV 280 nm,
flow rate 0.7 mL/min. (R) isomer, tr = 12.7 min and (S) isomer, tr
= 14.3.
5-[(2S)-1-(Benzyloxycarbonyl)pyrrolidin-2-yl]tetrazole (6): N-(Ben-
zyloxycarbonyl)-l-prolinenitrile (5) (11.5 g; 50 mmol), sodium az-
ide (6.5 g; 0.10 mol), zinc bromide (5.5; 24 mmol), 75 mL 2-propa-
nol and 150 mL water was added to a 500-mL round-bottomed
flask. The reaction mixture was stirred at reflux for 24 hours. To
the reaction was added 3 m HCl (100 mL). Stirring was continued
until no solid was present and the solution was clear. The organic
layer was isolated and the aqueous layer was extracted with ethyl
acetate (2×150 mL). The combined organic layers were washed
with brine (200 mL) and evaporated to give the title compound as
a pale yellow oil. The oil was triturated with petroleum ether and
evaporated to give a white, semi-crystalline rest (13.4 g; 98%). The
1H NMR and 13C NMR was identical to the previously reported
4-Hydroxy-4-(4Ј-methoxyphenyl)butan-2-one (9): Synthesized ac-
cording to GP1. 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole (80 mg; 0.12
mmol), DMSO/acetone (6 mL), 4-methoxybenzaldehyde (80 mg,
0.59 mmol), the mixture was stirred for 360 minutes. Column
chromatography (pentane/ethyl acetate, 3:2); yield 70 mg (62%); Rf
Eur. J. Org. Chem. 2005, 4287–4295
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4293

A. Hartikka, P. I. Arvidsson
FULL PAPER
= 0.44; direct infusion MS (CI) m/z (rel. intensity): 194.9 ([M + 1],
tane/ethyl acetate, 3:2); yield 63 mg (67%); Rf = 0.56; direct in-
6), 177.1 (76), 137.3 (100), 109.5 (32), 94.3 (22). 1H NMR and fusion MS (CI) m/z (rel. intensity): 165.0 ([M + 1], 2), 145.3 (82),
13C NMR spectroscopic data were identical to earlier published
results.[32] Enantiomeric excess was determined by HPLC (Daicel
103.4 (48), 77.31 (100). H NMR spectroscopic data were identical
1
to earlier published results.[33] 13C NMR (100 MHz, CDCl3): δ =
Chiralpak AS-H, iPrOH/hexane, 10:90), UV 254 nm, flow rate 1.0 30.7 (1 C), 51.9 (1 C), 69.8 (1 C), 126 (1 C), 127 (2 C), 128 (2 C),
mL/min. (R) isomer, tr = 15.4 min and (S) isomer, tr = 19.8 min.
142 (1 C), 209 (1 C) ppm. Enantiomeric excess was determined by
HPLC (Daicel Chiralpak AS, iPrOH/hexane, 10:90), UV 257 nm,
flow rate 1.0 mL/min. (R) isomer, tr = 15.5 min and (S) isomer, tr
= 19.8 min.
4-(4Ј-Bromophenyl)-4-hydroxybutan-2-one (10): Synthesized accord-
ing to GP1. 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole (0.08 mmol),
DMSO/acetone 4 mL, 4-bromobenzaldehyde (74 mg, 0.4 mmol),
the mixture was stirred for 150 minutes. Column chromatography
(pentane/ethyl acetate, 8:3); yield 65 mg (67%); Rf = 0.45; direct
infusion MS (CI) m/z (rel. intensity): 244.9 (M+1, 8), 226.0 (10),
185.2 (34), 145.4 (100), 117.4 (22), 78.7 (68). 1H NMR spectro-
scopic data were identical to earlier published results.[31] 13C NMR
(100 MHz, CDCl3): δ = 30.7 (1 C), 51.7 (1 C), 69.2 (1 C), 121 (1 C),
127 (2 C), 131 (2 C), 142 (1 C), 209 (1 C) ppm. Enantiomeric excess
was determined by HPLC (Daicel Chiralpak AS-H, iPrOH/hexane,
15:85), UV 220 nm, flow rate 1.0 mL/min. (R) isomer, tr = 11.1 min
and (S) isomer, tr = 13.6 min.
Computational Details: Density functional calculations were done
using Jaguar 5.5[34] on a PC equipped with dual Intel Xeon proces-
sors running Linux RedHat 9. Geometries were optimized at the
B3LYP/6-31G(d,p)[35] level of theory, and the vibrational fre-
quencies calculated to verify that all optimized structures repre-
sented minima or transition stated on the potential energy surface.
Single point energies in solution were computed using the B3LYP/
6-311+G(d,p) optimized structures at B3LYP/6-31+G(d,p) level of
theory using the self-consistent reaction field method as im-
plemented in Jaguar.
4-(3Ј-Bromophenyl)-4-hydroxybutan-2-one (11): Synthesized accord-
ing to GP1. 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole (0.04 mmol),
DMSO/acetone 4 mL, 3-bromobenzaldehyde (74 mg, 0.1 mmol),
the mixture was stirred for 140 minutes. Column chromatography
(pentane/ethyl acetate, 8:3); yield 61 mg (64%); Rf = 0.45; direct
infusion MS (CI) m/z (rel. intensity): 244.9 (M+1, 8), 226.0 (10),
185.2 (34), 145.4 (100), 117.4 (22), 78.7 (68). 1H NMR spectro-
scopic data were identical to earlier published results.[31] 13C NMR
(100 MHz, CDCl3): δ = 30.7 (1 C), 51.7 (1 C), 69.1 (1 C), 123 (1 C),
124 (1 C), 128 (1 C), 130 (1 C), 131 (1 C), 145 (1 C), 208 (1 C) ppm.
Enantiomeric excess was determined by HPLC (Daicel Chiralpak
AS-H, iPrOH/hexane, 10:90), UV 220 nm, flow rate 0.7 mL/min.
(R) isomer, tr = 20.74 min and (S) isomer, tr = 22.6 min.
NMR Spectroscopic Studies: The NMR spectroscopic studies were
performed by mixing l-proline (23.1 mg; 0.2 mmol) or 5-[(2S)-pyr-
rolidine-2-yl]-1H-tetrazole (27.8 mg; 0.2 mmol) and 1.0 mL dry
[D6]DMSO in an oven dried 10 mL round bottomed flask. The
mixtures were stirred for ca 10 h under argon atmosphere. To these
mixtures was added (17.3 mg; 21.72 μL; 0.2 mmol) of freshly dis-
tilled 2,2-dimethylpropionaldehyde. The mixtures were stirred for
2 h and 0.7 mL of the clear solution was transferred to a dry NMR
tube via a dry syringe. 1H NMR was recorded on both samples
showing extensive formation of the bicyclic oxazolidinone {3-tert-
butyl-tetrahydro-1H-pyrrolo[1,2-c][1,3]oxazol-1-one} in the former
case while no equivalent structure in the latter case. Another NMR
spectroscopic study was performed by mixing 5-[(2S)-pyrrolidine-
2-yl]-1H-tetrazole (2.5 mg; 0.018 mmol) and 1.0 mL dry [D6]
DMSO in an oven-dried 2-mL round-bottomed flask. The mixture
was stirred for ca 10 h under argon atmosphere. From this mixture
was transferred 0.6 mL to a dry NMR tube. To the sample was
added 0.11 mL of dried acetone via syringe. 1H NMR spectra using
suppression through the WET pulse sequence[21] was recorded and
did not indicate any formation of bicyclic oxazolidinone.
4-Hydroxy-4-methylhexan-2-one (12): Synthesized according to
GP1. 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole (16.8 mg; 0.12 mmol),
DMSO/acetone (6 mL), 2-methylpropionaldehyde (43.3 mg, 0.6
mmol), the mixture was stirred for 12 h. Column chromatography
(pentane/ethyl acetate, 4:1); yield 61.3 mg (79%); Rf = 0.32. 1H
NMR spectroscopic data were identical to earlier published re-
sults.[31] 13C NMR (100 MHz, CDCl3): δ = 17.7 (1 C), 18.3 (1 C),
30.8 (1 C), 33.0 (1 C), 46.9 (1 C), 72.2 (1 C), 210 (1 C) ppm. Enan-
tiomeric excess was determined by HPLC (Daicel Chiralpak AD,
iPrOH/hexane, 3:97), UV 280 nm, flow rate 0.7 mL/min. (R) iso-
mer, tr = 16.3 min and (S) Isomer, tr = 17.2.
Supporting Information Available: HPLC traces, 1H NMR, 13C
NMR spectra for key compounds and experiments together with
absolute energies and coordinates for the calculated structures (see
also the footnote on the first page of this article).
4-Hydroxy-4-(3Ј-methoxyphenyl)butan-2-one (13): Synthesized ac-
cording to GP1. 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole (16 mg;
0.118 mmol), DMSO/acetone (5.9 mL), 3-methoxybenzaldehyde
(80 mg, 0.59 mmol), the mixture was stirred for 240 minutes. Col-
umn chromatography (pentane/ethyl acetate, 3:2); yield 79 mg
(69%); Rf = 0.44; direct infusion MS (CI) m/z (rel. intensity): 194.9
([M + 1], 6), 177.1 (32), 137.3 (100), 109.5 (80), 94.3 (46), 78.3 (58).
1H NMR (500 MHz. CDCl3): δ = 2.2 (s, 3 H), 2.9 (m, 2 H), 3.4
(br. s, 1 H), 3.8 (s, 3 H), 5.2 (m, 1 H), 6.8 (ddd, J = 8.3, 2.6, 1.1, 1
H), 6.9 (m, 1 H), 7.2 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 30.7 (1 C), 52 (1 C), 55 (1 C), 69.7 (1 C), 111 (1 C), 113 (1 C),
118 (1 C), 130 (1 C), 144 (1 C), 160 (1 C), 209 (1 C) ppm. Enantio-
meric excess was determined by HPLC (Daicel Chiralpak AS,
iPrOH/hexane, 10:90), UV 254 nm, flow rate 0.7 mL/min. (R) iso-
mer, tr = 18.9 min and (S) isomer, tr = 24.1 min.
Acknowledgement
Financial support from The Swedish Research Council (VR) is
gratefully acknowledged.
[1] Comprehensive Organic Synthesis, vol. 2 (Eds.: B. M. Trost, I.
Fleming, C. H. Heathcock), Pergamon, Oxford, 1991.
[2] C. Palomo, M. Oiarbide, J. M. García, Chem. Soc. Rev. 2004,
33, 65.
[3] N. Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai, M. Shiba-
saki, J. Am. Chem. Soc. 1999, 121, 4168.
[4] B. M. Trost, H. Ito, J. Am. Chem. Soc. 2000, 122, 12003.
[5] J. Wagner, R. A. Lerner, C. F. Barbas III, Science 1995, 270,
1797.
[6] G. Zhong, T. Hoffmann, R. A. Lerner, S. Danishefsky, C. F.
Barbas III, J. Am. Chem. Soc. 1997, 119, 8131.
[7] U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed. Engl.
1971, 10, 496.
4-Hydroxy-4-phenylbutan-2-one (14): Synthesized according to
GP1. 5-[(2S)-pyrrolidine-2-yl]-1H-tetrazole (16 mg; 0.118 mmol),
DMSO/acetone (5.9 mL), benzaldehyde (66 mg, 0.59 mmol), the
mixture was stirred for 240 minutes. Column chromatography (pen-
4294
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 4287–4295

5-(Pyrrolidine-2-yl)tetrazole
FULL PAPER
[8]
[9]
D. M. Spero, S. R. Kapadia, J. Org. Chem. 1996, 61, 7398; d)
G. A. Olah, S. Narang, A. P. Fung, G. B. Gupta, Synthesis
1980, 8, 657; e) Z. P. Demko, K. B. Sharpless, Org. Lett. 2002,
4, 2525; f) R. Huisgen, Pure Appl. Chem. 1989, 61, 613; g)
G. R. Almquist, W. Chao, C. White-Jennings, J. Med. Chem.
1985, 28, 1067.
B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc. 2000,
122, 2395.
a) B. List, Acc. Chem. Res. 2004, 37, 548; b) N. Vignola, B.
List, J. Am. Chem. Soc. 2004, 126, 450; c) N. Mase, F. Tanaka,
C. F. Barbas III, Angew. Chem. Int. Ed. 2004, 43, 2424; d) R.
Thayumanavan, F. Tanaka, C. F. Barbas III, Org. Lett. 2004,
6, 20; R. Thayumanavan, F. Tanaka, C. F. Barbas III, Org.
Lett. 2004, 6, 3541; e) S. P. Brown, M. P. Brochu, C. J. Sinz,
D. W. C. MacMillan, J. Am. Chem. Soc. 2003, 125, 10808; f)
A. B. Northrup, D. W. C. MacMillan, J. Am. Chem. Soc. 2002,
124, 6798; g) A. Bøgevig, K. Juhl, N. Kumaragurubaran, W.
Zhuang, K. J. Jørgensen, Angew. Chem. Int. Ed. 2002, 41, 1790;
h) A. Córdova, H. Sundén, M. Engqvist, I. Ibrahem, J. Casas,
J. Am. Chem. Soc. 2004, 126, 8914; i) A. Bøgevig, H. Sundén,
A. Córdova, Angew. Chem. Int. Ed. 2004, 43, 1109.
a) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43,
5138; b) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001,
40, 3726; c) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719;
d) N. Mase, F. Tanaka, C. F. Barbas III, Angew. Chem. Int. Ed.
2004, 43, 2420; e) E. R. Jarvo, S. J. Miller, Tetrahedron 2002,
58, 2481; f) W. Notz, F. Tanaka, C. F. Barbas III, Acc. Chem.
Res. 2004, 37, 580; g) M. Marigo, T. C. Wabnitz, D. Fielen-
bach, K. A. Jørgensen, Angew. Chem. Int. Ed. 2005, 44, 794;
h) M. P. Brochu, S. P. Brown, D. W. C. MacMillan, J. Am.
Chem. Soc. 2004, 126, 4108; i) M. Engqvist, J. Casas, H.
Sundén, I. Ibrahem, A. Córdova, Tetrahedron Lett. 2004, 43,
1109.
[21] S. H. Smallcombe, S. L. Patt, P. A. Keifer, J. Magn. Reson. Ser.
A 1995, 117, 295.
[22] a) K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J. Am. Chem.
Soc. 2001, 123, 3220; b) T. J. Dickerson, K. D. Janda, J. Am.
Chem. Soc. 2002, 124, 3220.
[23] a) S. Bahmanyar, K. N. Houk, J. Am. Chem. Soc. 2001, 123,
12911; b) F. R. Clemente, K. N. Houk, Angew. Chem. Int. Ed.
2004, 43, 5766.
[24] a) S. Bahmanayar, K. N. Houk, J. Am. Chem. Soc. 2001, 123,
11273; b) K. N. Rankin, J. W. Gauld, R. J. Boyd, J. Phys.
Chem. A. 2002, 106, 5155; c) S. Bahmanayar, K. N. Houk, H. J.
Martin, B. List, J. Am. Chem. Soc. 2003, 125, 2475; d) C. Alle-
mann, R. Gordillo, F. R. Clemente, P. H.-Y. Cheong, K. N.
Houk, Acc. Chem. Res. 2004, 37, 558.
[25] a) B. Marten, K. Kim, C. Cortis, R. A. Friesner, R. B. Murphy,
M. N. Ringnalda, D. Sitkoff, B. Honig, J. Phys. Chem. 1996,
100, 11775; b) D. J. Tannor, B. Marten, R. Murphy, R. A.
Friesner, D. Sitkoff, A. Nicholls, M. Ringnalda, W. A. God-
dard III, B. Honig, J. Am. Chem. Soc. 1994, 116, 11875.
[26] a) B. List, L. Hoang, H. J. Martin, Proc. Natl. Acad. Sci. USA
2004, 101, 5839; b) D. Seebach, M. Boes, R. Naef, W. B.
Schweizer, J. Am. Chem. Soc. 1983, 105, 5390.
[27] a) S. P. Mathew, H. Iwamura, D. G. Blackmond, Angew. Chem.
Int. Ed. 2004, 43, 3317; b) H. Iwamura, S. P. Mathew, D. G.
Blackmond, J. Am. Chem. Soc. 2004, 126, 11770; c) H. Iwa-
mura, D. H. Wells, S. P. Mathew, M. Klussmann, A. Armos-
trong, D. G. Blackmond, J. Am. Chem. Soc. 2004, 126, 16312.
[28] F. Orsini, F. Pelizzoni, M. Forte, M. Jisti, G. Bombieri, F. Bene-
tello, J. Heterocycl. Chem. 1989, 26, 837.
[10]
[11]
[12]
[13]
A. Berkessel, B. Koch, J. Lex, Adv. Synth. Catal. 2004, 346,
1141.
P. Krattinger, R. Kovasy, J. D. Revell, S. Ivan, H. Wennemers,
Org. Lett. 2005, 7, 1101.
A. J. A. Cobb, D. M. Shaw, S. V. Ley, Synlett 2004, 3, 558.
[14] H. Torii, M. Nakadai, K. Ishihara, S. Saito, H. Yamamoto,
Angew. Chem. Int. Ed. 2004, 43, 1983.
[15] A. Hartikka, P. I. Arvidsson, Tetrahedron: Asymmetry 2004,
[29] M. T. Rispens, O. J. Gelling, A. H. M. D. Vries, A. Meetsma,
F. Van Bolhuis, B. L. Feringa, Tetrahedron 1996, 52, 3521.
[30] M. C. Bagley, R. T. Buck, S. L. Hind, C. J. Moody, J. Chem.
Soc., Faraday Trans. 1 1998, 3, 591.
15, 1831.
[16] A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold, S. V.
Ley, Org. Biomol. Chem. 2005, 3, 84.
[17] a) N. Momiyama, H. Torii, S. Saito, H. Yamamoto, Proc. Natl.
Acad. Sci. USA 2004, 101, 5274; b) Y. Yamamoto, N. Momi-
yama, H. Yamamoto, J. Am. Chem. Soc. 2004, 126, 5962.
[18] N. S. Chowdari, C. F. Barbas III, Org. Lett. 2005, 7, 867.
[31] Z. Tang, F. Jiang, L. T. Zu, Z. Cui, L. Z. Gong, A. Q. Mi, Y. Z.
Jiang, Y. D. Wu, J. Am. Chem. Soc. 2003, 125, 5262.
[32] K. D. Janda, A. Cordova, J. Am. Chem. Soc. 2001, 123, 8248.
[33] S. E. Denmark, J. R. Heemstra Jr., Org. Lett. 2003, 13, 2303.
[19] A. J. A. Cobb, D. A. Longbottom, D. M. Shaw, S. V. Ley, [34] Jaguar 5.5, Schrödinger, L. L. C., Portland, OR, 1991–2003.
Chem. Commun. 2004, 1808.
[20] a) E. J. Corey, S. Shibata, R. K. Bakshi, J. Org. Chem. 1988,
53, 2861; b) V. F. Pozdnev, Tetrahedron Lett. 1995, 36, 7115; c)
[35] A. D. Becke, J. Chem. Phys. 1993, 98, 5648.
Received: June 27, 2005
Published Online: August 29, 2005
Eur. J. Org. Chem. 2005, 4287–4295
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4295