Synthesis and application of novel imidazole and 1H-tetrazolic acid containing catalysts in enantioselective organocatalyzed Diels-Alder reactions

Article abstract of DOI:10.1016/j.tetasy.2009.07.029

Herein we report studies on the organocatalytic Diels-Alder reaction using a variety of catalysts capable of activating α,β-unsaturated carbonyl compounds for reactions with dienes. The structurally attractive catalysts 4 and 14 were utilized in the enant

Full text of DOI:10.1016/j.tetasy.2009.07.029

Tetrahedron: Asymmetry 20 (2009) 1871–1876
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis and application of novel imidazole and 1H-tetrazolic acid
containing catalysts in enantioselective organocatalyzed Diels–Alder reactions
Antti Hartikka a, Leila Hojabri a, , Partha Pratim Bose a, Per I. Arvidsson a,b,
*
a Department of Biochemistry and Organic Chemistry, Uppsala University Box 576, SE-751 23 Uppsala, Sweden
b Discovery CNS and Pain Control, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report studies on the organocatalytic Diels–Alder reaction using a variety of catalysts capable
Received 15 June 2009
Accepted 23 July 2009
Available online 2 September 2009
of activating a,b-unsaturated carbonyl compounds for reactions with dienes. The structurally attractive
catalysts 4 and 14 were utilized in the enantioselective organocatalytic Diels–Alder reactions. Catalyst
4 provided the products in fair yields and more importantly in good enantioselectivities of up to 83%
ee. Catalyst 14 was synthesized in high yield and was assessed in the enantioselective organocatalytic
Diels–Alder reaction. Catalyst 14 proved to be a highly active and selective catalyst providing the prod-
ucts in high yield and high enantioselectivities up to 95% ee.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Substrate
Catalyst
LUMO-activation
LA
Lewis acid (LA)
The enantioselective Diels–Alder reaction has attracted much
interest over the past twenty years. The asymmetric catalysis of
Diels–Alder reactions mediated by chiral Lewis acids, including
early transition metals, has dominated this field at the outset.1
However, the enantioselective organocatalytic Diels–Alder reac-
tion discovered by MacMillan has changed the way chemists
think about conducting asymmetric catalysis,2 and was one of
the first studies3 that attracted interest in the area of asymmetric
organocatalysis.4
O
O
+
R
R
R
* HCl
N
H
N
+
O
R
Figure 1. Comparision between Lewis acid and organocatalytic LUMO activation of
,b-unsaturated aldehydes.
a
The concept of organocatalytic enantioselective Diels–Alder
reactions5 catalyzed by chiral-secondary-amine-containing mole-
cules relies on the reversible covalent attachment of the catalyst
to a,b-unsaturated aldehydes, leading to iminium ions. This in turn
leads to LUMO-lowering activation (Fig. 1), and significantly in-
case, the stereocontrolling elements include the selective forma-
tion of (E)-iminium isomers to avoid non-bonding interactions be-
tween the substrate olefin and geminal methyl substituents, and
the benzyl group on the catalyst that effectively shields the Re-face
of the dienophile, leaving the Si-face exposed (Fig. 2).6,8
creases the reactivity of the parent dienophile toward reaction
with the diene.6 The increased reactivity of
a,b-unsaturated imin-
O
ium ions in Diels–Alder reactions was first reported some thirty
O
years ago.7
N
N
+
N
Important aspects of MacMillan’s initial catalyst design include
the control of iminium-ion geometry and enantiofacial discrimina-
tion with respect to the incoming diene.8 MacMillans original cat-
alyst 1, has proven to be a highly active and selective catalyst for
the enantioselective organocatalytic Diels–Alder reaction. In this
+
N
Ph
R
Ph
R
(E)-iminium ion is preferred
Si-phase attack favored
* Corresponding author. Tel.: +46 18 471 3800; fax: +46 18 471 3818.
E-mail addresses: Per.Arvidsson@biorg.uu.se, Per.Arvidsson@astrazeneca.com
(P.I. Arvidsson).
Visiting PhD student at UU 2005/2006 from Sharif University of Technology,
Theran, Iran.
Figure 2. Catalyst (5S)-5-benzyl-2,2,3-trimethylimidazolidin-4-one 1, developed
by MacMillan et al. for the enantioselective Diels–Alder reaction.2 The figure shows
the preferred (E)-iminium ion after reaction with the a,b-unsaturated aldehyde.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.07.029

1872
A. Hartikka et al. / Tetrahedron: Asymmetry 20 (2009) 1871–1876
As part of our ongoing efforts to optimize organocatalysts for
enantiomeric excesses. The low enantioselectivity of the reaction
can be explained by the fact that catalyst 2 lacks the two methyl
various enantioselective reactions,9 we became interested in
testing the catalysts available in house in the organocatalytic
asymmetric Diels–Alder reaction. Herein we wish to report our
findings in this area.
groups at the
a-position with respect to the secondary amine,
which are necessary for controlling the iminium-ion geometry.
The selective (E)-iminium isomer formation plays an important
role in determining the degree of enantioselective induction. We
therefore reasoned out that a re-design of catalyst 2 to more clo-
sely match catalyst 1, should lead to a novel catalyst (i.e., 14) in
which both the vital di-methyl motif and the beneficial 1H-
tetrazole moiety are present. Catalyst 14 was synthesized from
2. Results and discussion
During the course of our work in the area of organocatalysis we
have prepared a variety of catalysts i.e. 1–4 (Fig. 3). Catalyst 1 rep-
resents the original MacMillan catalyst,2 especially designed for
the Diels–Alder reaction. Catalyst 2 is the tetrazolic acid analogue
commercially available N -(9-fluorenylmethoxycarbonyl)-N -tri-
a
c
tyl-
L
-asparagine according to Scheme 1.
The synthesis made use of the highly sterically demanding Trt
group in order to differentiate between the two amide groups dur-
ing the cyclization leading to the imidazolidinone. The synthesis
of L-proline, which was originally described by Ley et al., Yamam-
oto et al., and by us for the organocatalytic aldol reaction.10 This
catalyst has since then been widely used in the organocatalytic
community for a variety of purposes.11 Catalyst 3 is the homolo-
gated tetrazole analogue originally described by Ley et al.12 The
imidazole containing catalyst 4 was designed by us,13 especially
started from commercially available N -(9-fluorenylmethoxycar-
a
bonyl)-N -trityl-L-asparagine 8, which has a Fmoc-protected amine
c
functionality and a bulky trityl protecting group on the amide.
Staring material 8 was converted to methyl amide 9 in 88% isolated
yield using an analogous route to that reported by Biondi et al.14
The Fmoc group was selectively cleaved using 20% piperidine in
DMF to furnish the free amine 10 in high yield after column chro-
matography. The next step involved acid-catalyzed imine forma-
tion with acetone, followed by cyclization to the five-membered
imidazolidinone 11 in 95% isolated yield. The trityl group of 11
seems to have an important effect on the reaction by firstly pre-
venting cyclization to the six-membered ring through the other
amide, and secondly by favoring the cyclized product 11, presum-
ably via a six-membered intramolecular hydrogen bond between
the imidazolidinone nitrogen and the side-chain amide bond that
diminishes steric interactions between the bulky Trt-group and
the imidazolidinone ring. The trityl group was then cleaved off in
refluxing TFA to give 12. Dehydration, using a modified procedure
including 4 Å MS in DMF and 1.5 equiv of cyanuric chloride, pro-
vided nitrile 13 in 85% isolated yield. The nitrile 13 was converted
to the tetrazolic acid 14 in 71% yield (Scheme 1). The addition of
HCl in methanol gave the salt of the catalyst, that is, 14a, which
was assessed in the enantioselective organocatalytic Diels–Alder
reaction of various dienophiles with cyclopentadiene (Table 3).
As can be seen in Table 3, the new catalyst facilitates the enan-
tioselective organocatalytic Diels–Alder cycloaddition reaction in a
highly stereoselective manner. The Diels–Alder adducts were ob-
tained in high yields and enantioselectivities for both aliphatic
and aromatic dienophiles (Table 3, entries 1–4). This catalyst also
offered an increased diastereoselectivity, as compared to catalysts
1 and 4 (Tables 1 and 2) for most substrates, with the exo-isomer
being the major product. In contrast to catalysts 4, the new catalyst
14 provided the endo-isomer in higher enantiomeric excess than
the exo-isomer. This outcome correlates to the results reported
for catalyst 1 (Table 1 and Ref. 2a), suggesting that the organiza-
tional control imposed in the transition state by the two methyl
groups in the original MacMillan catalysts is effective also in the
new catalyst 14.
for the organocatalytic addition of nitro-alkanes to
aldehydes.
The potential of these catalysts to facilitate the reaction be-
tween trans-2-hexenal 5 and cyclopentadiene 6 to give cycloaddi-
tion products 7 was investigated (Table 1).
a,b-unsaturated
The results as shown in Table 1 reveal several interesting issues.
As previously known, catalyst 1 developed by MacMillan provides
a high reaction rate and excellent enantioselectivity. Catalyst 1 was
also shown to react well in an acetonitrile/water mixture (cf. en-
tries 1 and 2) albeit with a slightly lower conversion; this proce-
dure greatly simplifies the work-up in preparative applications,
as no hydrolysis of the dimethyl-acetal formed in MeOH solution
is needed. Interestingly, catalyst 4 showed promising results,
which prompted us to evaluate this catalyst further.
Catalyst 4 also worked in both MeOH and acetonitrile solutions.
The TFA salt of 4 gave a slightly better conversion (approx. 5%) in
MeCN, as compared to MeOH, while the HCl salt provided better
conversions in MeOH. We therefore evaluated both the HCl salt
and the TFA salt of catalyst 4 in the Diels–Alder reaction between
cyclopentadiene and the three
shown in Table 2.
a,b-unsaturated aldehydes as
As can be seen in Table 2, the isolated yields obtained with cat-
alyst 4 are fair, although apparently a lot of product was lost during
the isolation (cf. Table 1, entry 16 and Table 2, entry 2). Still, the
Diels–Alder adducts were obtained in fair yields and moderate-
to-high enantiomeric excesses for both aliphatic and aromatic
dienophiles. The diastereoselectivity, between the exo- and endo-
products, was poor with this catalyst, just as observed with the
MacMillan catalyst 1 for these substrates.2a Catalyst 4 continuously
provided the exo-isomer in higher enantiomeric excess than the
endo-products (Table 2, entries 1–6).
The initial investigation presented in Table 1 revealed other
interesting data. It can be seen that the tetrazole containing cata-
lyst 2 offers very high reactivity, in most cases matching the reac-
tivity of catalyst 1, but provides Diels–Alder adducts in low
O
N
O
N
N
N
N
H
N
H
N
H
N
H
HN
N
N
N
HN
NH
4a = 2·HCl
4b = 2·TFA
2
3a = HCl
1 = HCl
N
N
2a = HCl
2b = TFA
3b = TFA
Figure 3. Molecular structures of the catalysts assessed (alphabetic characters label different salt-forms).

A. Hartikka et al. / Tetrahedron: Asymmetry 20 (2009) 1871–1876
1873
Table 1
Organocatalyzed [4+2] cycloaddition between trans-2-hexenal 5 and cyclopentadiene 6 to give cycloaddition products exo- and endo-7 using catalysts 1–4 in various solvents
5 mol% Catalyst 1-4
n-Pr
O
+
n-Pr
CHO
CHO
n-Pr
Solvent
(2S)-exo-7
(2S)-endo-7
5
6
Entry
Solvent
HClg
Time (h)
Catalyst
Conversion (%)
Yieldh (%)
exo:endoi
eej exo-7 (%)
eej endo-7 (%)
1a
CH3OHd
—
—
—
—
—
—
1
2
2
34
34
34
2
2
4
2
2
2
1
2
4
2
2
1
1
2
2
2
2a
2a
2a
2a
2a
2a
2a
2b
3a
3b
4a
99
69
—
—
—
68
65
—
98
89
99
99
94
—
—
—
12
4
1.05:1
1.1:1
1.7:1
1.6:1
1.7:1
1.9:1
1.9:1
1.7:1
1.7:1
1.7:1
3.3:1
3.6:1
1.9:1
3.6:1
1.7:1
1.2:1
86
79
0
0
0
36
19
19
17
9
3
3
43
3
17
56
96
96
2
2
5
36
10
8
10
8
4
0
41
0
9
2a
CH3CNd
3b
CHCl3
f
4b
DMFf
5b
THFf
4
6a
CH3CNd
CH3CNd
CH3CNe
CH3CNd
CH3CNd
CH3CNd
CH3CNd
CH3CNd
CH3CNe
CH3CNd
CH3OHd
—
—
59
—
—
—
—
—
42
—
—
7a
8b
1
2
9a
10a
11a
12a
13a
14c
15a
16a
10
20
40
—
1
—
—
54
85
76
a
b
c
d
e
f
The reaction was performed by using trans-2-hexenal (0.61 mmol), cyclopentadiene (1.83 mmol) and catalyst (0.031 mmol).
The reaction was performed with trans-2-hexenal (1.22 mmol), cyclopentadiene (3.66 mmol) and catalyst (0.061 mmol).
The reaction was performed by using trans-2-hexenal (1.22 mmol), cyclopentadiene (2.44 mmol) and catalyst (0.061 mmol).
30.5 lL of the solution of solvent/H2O 95/5.
61
lL of the solution of solvent/H2O 95/5.
61
lL of the solvent without any water.
g
h
i
Equivalents of HCl(37%) to catalyst.
Isolated yield after column chromatography.
The product ratios were determined by correlation of retention times in GC analysis to product mixtures obtained from the reaction with catalyst 1.
Absolute and relative configurations were determined by correlation of GC retention times. The absolute and relative configurations were initially determined by
j
chemical correlation to known compounds.
Table 2
Organocatalyzed Diels–Alder cycloadditions between cyclopentadiene 6 and representative dienophiles utilizing catalysts 4
O
O
N
N
R
CHO
(2S)-endo
R
O
5 mol % 4a or 4b
N
H
N
H
+
a) CH3OH:H2O or
b) CH3CN:H2O
·2TFA
·2HCl
NH
NH
N
N
CHO
24 h
R
4a
4b
(2S)-exo
Entrya
R
Solventb
Catalyst
Yieldc
exo:endod
exo eee (%)
endo eee (%)
1
2
3
4
5
6
Me
n-Pr
Ph
Me
n-Pr
Ph
CH3OH
CH3OH
CH3OH
CH3CN
CH3CN
CH3CN
4a
4a
4a
4b
4b
4b
45
49
52
72
61
75
1.1:1
1.2:1
1.2:1
1.25:1
1:1
66 (2S)
69 (2S)
68 (2S)
89 (2S)
72 (2S)
84 (2S)
57 (2S)
58 (2S)
60 (2S)
83 (2S)
45 (2S)
58 (2S)
1.1:1
a
b
c
Reaction was performed at 23 °C.
Each reaction was performed in 61
Isolated yield after column chromatography.
The product ratios were determined by correlation of GC retention times to product mixtures obtained from reaction with catalyst 1.
Absolute and relative configurations were determined by correlation of GC retention times. The absolute and relative configurations were initially determined by
l
L of a (95:5) MeOH/MeCN:H2O mixture.
d
e
chemical correlation to known compounds.
in the asymmetric conjugate addition of nitroalkanes to enals can
thus successfully be employed in the enantioselective organocata-
lytic Diels–Alder reaction as well.
In the second part of this study a highly potent and selective cat-
alyst was developed for the enantioselective organocatalytic Diels–
Alder reaction. The new catalyst possesses a functional tetrazole
3. Conclusion
We have shown that the side-chain modification of catalyst 1 to
include an imidazole function rather than a phenyl group, that is,
yielding catalyst 4, did not seriously affect the stereoselectivity of
the Diels–Alder reaction. The catalyst originally designed for use

1874
A. Hartikka et al. / Tetrahedron: Asymmetry 20 (2009) 1871–1876
Ph
Trt
NH
O
Trt
NH
O
Ph
Ph
O
N
H
O
H
N
H
N
i
ii
Fmoc
OH
H2N
N
H
O
N
H
88%
86%
O
O
O
8
9
10
O
O
O
N
N
N
N
H
N
iii
N
v
iv
60%
NC
H
H
O
O
95%
85%
NH
Trt
NH2
11
13
12
O
N
N
vi
H
N
N
71%
NH
N
14
vii
quant.
14a = HCl
Scheme 1. Reagents and conditions: (i) HOBTꢀH2NMe, EDC, DMF, rt, 24 h (ii) 20% piperidine in DMF, rt (iii) acetone, p-TsOH, MeOH, reflux, 12 h; (iv) 100% TFA, reflux, 10 h; (v)
cyanuric chloride, 4 Å MS, DMF, 100 °C, 24 h; (vi) NaN3, NH4Cl, DMF, 95 °C, 12 h; and (vii) 2 M HCl in MeOH, DEE, rt, 5 min.
Table 3
Results from the enantioselective organocatalyzed Diels–Alder cycloaddition utilizing catalyst 14
O
N
R
O
5 mol % 14a
+
+
R
CHO
N
H
CH3OH:H2O
24h
CHO
R
*HCl
N
NH
N N
(2S)-exo
(2S)-endo
14a
Entrya
R
Yieldb
exo:endoc
exo eed (%)
endo eed (%)
1
2
3
4
Me
86
83
92
89
1.3:1
1.5:1
1:1
90 (2S)
85 (2S)
92 (2S)
89 (2S)
95 (2S)
93 (2S)
92 (2S)
90 (2S)
n-Pr
i-Pr
Ph
1.5:1
a
b
c
Reaction was performed at 23 °C.
Isolated yield after column chromatography.
The product ratios were determined by correlation of GC retention time to product mixtures obtained from the reaction with catalyst 1.
d
Absolute and relative configurations were determined by correlation of GC retention time. The absolute and relative configurations were initially determined by chemical
correlation to known compounds.
motif combined with the organizational control imposed by the
catalyst core. These favorable structural features should make
the new catalyst 14 highly interesting for other enantioselective
organocatalytic reactions.
visualized either with UV light, by heating after soaking the TLC
plate in a solution consisting of 0.5% 2,4-dinitrophenylhydrazine
in 2 M HCl, by a ninhydrine solution or by an ethanol solution of
phosphomolybdic acid. Column chromatography was performed
on silica gel (MatrexTM 60A, 37–0
lm) and preparative reversed
phase chromatography was carried out using a MEGA BOND ELUT
(Varian) SS-C18 Cartridge (1 g, 6 mL, 60 Å.). 1H NMR 500 MHz and
1H 300 MHz spectra were recorded on a Varian Unity 500 MHz and
Varian Mercury plus 300 MHz spectrometer, respectively; 13C NMR
75 MHz spectra were recorded on a Varian Mercury plus 300 MHz
spectrometer. All spectra were acquired at ambient temperature.
Chemical shifts (d) in ppm are reported using residual chloroform,
dimethylsulfoxide or methanol as an internal reference (1H d 7.26,
4. Experimental
4.1. General
Chemicals and solvents were either purchased pure from com-
mercial suppliers or purified by standard techniques. For thin layer
chromatography (TLC), precoated 0.25 mm silica plates (Mache-
rey-Nagel 60 AlugramÒ Sil G/UV254) were used and spots were

A. Hartikka et al. / Tetrahedron: Asymmetry 20 (2009) 1871–1876
1875
13C d 77.0), (1H d 2.49, 13C d 39.5) or (1H d 3.30, 13C d 49.0)
and coupling constants (J) are given in hertz. Infrared spectra
were recorded on a Perkin–Elmer Spectrum 100 FT/IR spectrome-
ter. Optical rotation measurements were carried out using a Per-
kin–Elmer 241 spectropolarimeter. The purity of catalysts and
intermediates was confirmed by means of a high pressure liquid
chromatography (HPLC) system coupled to a MS detector and an
evaporative light-scattering detector (ELSD); the system consisted
of a Gilson 322 pump, Gilson 233 XL autosampler and a Gilson UV/
VIS 152 detector, coupled in series with a Finnigan AQA mass spec-
trometer and an ELSD (Sedex 85 CC) from Sedere. GC–MS determi-
nation of enantiomeric excesses was done using a Varian CP-8410
auto injector and a Varian Saturn 2100T GC–MS system equipped
reflux for 12 h after which the solution was allowed to reach room
temperature. The solution was concentrated under reduced pres-
sure to give a light yellow residue which was further purified by
means of column chromatography (silica gel, 10% MeOH in
DCM), Rf = 0.55, to give the product as a white powder (4.56 g;
92%). 1H NMR (500 MHz, DMSO-d6) d 1.20 (d, J = 4.2 Hz, 6 H),
2.50 (d, J = 6.1 Hz, 2H), 2.70 (s, 3H), 3.12 (d, J = 9 Hz, 1H), 3.68
(m, 1H), 7.17–7.21 (m, 9H), 7.24–7.28 (m, 6H), 8.86 (s, 1H); 13C
NMR (75 MHz, DMSO-d6) d 25.3 (1C), 25.6 (1C), 27.9 (1C), 49.5
(1C), 56.0 (1C), 70.3 (1C), 76.0 (1C), 127.3 (6C), 128.4 (6C), 129.4
(3C), 145.7 (3C), 170.5 (1C), 173.5 (1C); ESI-MS: m/z calcd for
C27H29N3O2: 427; found 428 [M+H]+, 450 [M+Na]+, 775 [2 M+Na]+;
½
a 2D3
ꢁ
¼ ꢂ25:6 (c 1, MeOH).
*
with an Astec Chiraldex gamma-TA column (30 m 0.25 mm), with
helium gas at 10 psi as a carrier gas and electron impact ionization
(EI, 70 eV). Chromatograms and retention times for all chiral prod-
ucts were comparable to those reported in Ref. 2a.
4.2.2.4. (5S)-5-(Acetamide-5-yl)-2,2,3-trimethyl-imidazolidin-
4-one 12. To (5S)-5-(N-trimethylacetamide-5-yl)-2,2,3-trimethyl-
imidazolidin-4-one 11 (2.25 g; 5.27 mmol) was added 40 ml TFA.
The resulting yellow mixture was stirred at reflux for 10 h. The
mixture was allowed to cool to room temperature after which
TFA was removed under reduced pressure. The residue was further
purified by means of column chromatography (silica gel, 20%
MeOH in DCM), Rf = 0.23, to give the product as a colorless oil
(0.56 g; 60%). 1H NMR (500 MHz, DMSO-d6) d 1.20 (s, 3H), 1.26
(s, 3H), 2.15 (dd, J = 15.1, 9.0 Hz, 1H), 2.43 (dd, J = 15.1, 3.7 Hz,
1H), 2.64 (s, 3H), 3.02 (br s, 1H), 3.70 (d, J = 6.2 Hz, 1H), 6.80 (s,
1H), 7.40 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d 25.2 (1C), 25.3
(1C), 27.9 (1C), 49.3 (1C), 55.7 (1C), 75.7 (1C), 173.0 (1C), 173.5
(1C); ESI-MS: m/z calcd for C8H15N3O2: 185; found 186 [M+H]+;
4.2. General procedure for catalytic asymmetric cycloaddition
reactions
To a vial containing the catalyst (0.061 mmol) as a 1 M solution
in CH3OH/H2O (95/5 v/v) or MeCN/H2O (95/5 v/v) were added
the
a,b-unsaturated aldehyde (1.22 mmol) and cyclopentadiene
(302
lL; 3.66 mmol). After consumption of the limiting reagent,
the reaction mixture was diluted with Et2O and washed succes-
sively with H2O and brine. The organic layer was dried (Na2SO4),
filtered, and concentrated. When MeOH was used as solvent, the
product was isolated as the dimethyl acetal, which was hydrolyzed
by stirring the product mixture in TFA/H2O/CHCl3 (1:1:2) for 2 h at
room temperature, followed by neutralization with satd aq NaH-
CO3 and extraction with Et2O. The resulting mixture was purified
by silica gel chromatography and analyzed as described in the
supporting information to Ref. 2a.
½
a 2D3
ꢁ
¼ þ11:6 (c 2.85, MeOH).
4.2.2.5. (5S)-5-(Acetonitrile-5-yl)-2,2,3-trimethyl-imidazolidin-
4-one 13. To a mixture of (5S)-5-(acetamide-5-yl)-2,2,3-trimethyl-
imidazolidin-4-one 12 (1.5 g; 8.1 mmol) in 15 mL DMF was added
approximately2 gof4 ÅMS. Themixturewasstirredfor10 minafter
which cyanuric chloride (2.3 g; 12.1 mmol) was added. The mixture
was stirred for 1 h at room temperature after which the mixture was
stirred at 100 °C for 12 h. The mixture was allowed to reach room
temperature, and concentrated under reduced pressure to give a
reddish oil. The crude product was purified by means of column
chromatography (silica gel, 5% MeOH in DCM), Rf = 0.45, to give
product as colorless oil (1.15 g; 85%). 1H NMR (500 MHz, DMSO-
d6) d 1.67 (s, 3H), 1.73 (s, 3H), 2.86 (s, 3H), 3.11 (dd, J = 18, 5.9 Hz,
1H), 3.28 (dd, J = 18, 2.2 Hz, 1H), 4.85 (d, J = 4.2 Hz, 1H); 13C NMR
(75 MHz, DMSO-d6) d 22.2 (1C), 22.5 (1C), 23.3 (1C), 24.7 (1C), 54.9
(1C), 81.5 (1C), 117.0 (1C), 164.3 (1C); ESI-MS: m/z calcd for
4.2.1. Synthesis of catalysts 1–4
These catalysts were prepared as described in the references
provided for each catalyst in the main text above.
4.2.2. Synthesis of catalysts 14
4.2.2.1. Methyl-(2S)-(9H-fluoren-9-yl)-1-(methylamino)-1,4-dioxo-
4-tritylamino-2-ylcarbamat 9. The material was prepared from
commercially available N -(9-fluorenylmethoxycarbonyl)-N -tri-
a
c
tyl-L
-asparagine in analogy to a known literature procedure.14
4.2.2.2. Methyl-(2S)-2-amino-N1-methyl-N4-tritylsuccinamide
10. To the crystalline 9 (17.7 g; 29 mmol), obtained above, was
added 100 mL of 20% piperidine in DMF. The resulting mixture
was stirred at room temperature for 2 h after which the solution
was concentrated under reduced pressure to give a yellow residue
which was further purified by means of column chromatography
(silica gel; 5% MeOH in DCM), Rf = 0.2, to give the product as a
white powder (9.89 g; 88%). 1H NMR (500 MHz, DMSO-d6) d 1.90
(s, 2H), 2.42 (d, J = 7 Hz, 2H), 2.58 (d, J = 4.6 Hz, 3H), 3.44 (t, J =
6.7 Hz, 1H), 7.17–7.21 (m, 9H), 7.24–7.30 (m, 6H), 7.82 (dd, J =
10.2, 4.6 Hz, 1H), 9.18 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d
25.5 (1C), 41.3 (1C), 52.0 (1C), 69.2 (1C), 126.3 (6C), 127.4 (6C),
128.5 (3C), 145.0 (3C), 170.1 (1C), 174.4 (1C); ESI-MS: m/z calcd
C8H13N3O: 167; found 168 [M+H]+; ½a D23
¼ þ112:1 (c 1.8, MeOH).
ꢁ
4.2.2.6. (5S)-5-((1H-Tetrazole-5-yl)methyl)-2,2,3-trimethyl-imi-
dazolidin-4-one 14. To a mixture of (5S)-5-(acetonitrile-5-yl)-2,2,
3-trimethyl-imidazolidin-4-one 13 (200 mg; 1.2 mmol) in 5 mL
DMF were added sodium azide (95 mg; 1.3 mmol) and ammo-
nium chloride (2.4 mmol; 0.13 g). The mixture was stirred at
95 °C for 10 h after which the mixture was allowed to cool
down to room temperature. The solution was concentrated un-
der reduced pressure to give a light-brown oil. Purification of
this oil was performed using preparative reversed-phase chro-
matography on a SS-C18 cartridge (1 g, 6 mL, 60 Å) (gradient:
20–90% acetonitrile–water, with the product eluting at 80% ace-
for C24H25N3O2: 387; found 388 [M+H]+, 775 [2 M+H]+; ½a 2D3
ꢁ
¼
tonitrile), to provide after concentration a white crystalline
ꢂ1:1 (c 1, MeOH).
mass. 1H NMR (500 MHz, DMSO-d6) d 1.71 (s, 3H), 1.80 (s,
3H), 2.90 (s, 3H), 3.20 (dd, J = 16.5, 4.3 Hz, 1H), 3.40 (dd,
J = 16.5, 2.4 Hz, 1H), 4.80 (d, J = 4.5 Hz, 1H), 9.20 (br s, 1H);
13C NMR (75 MHz, DMSO-d6) d 22.2 (1C), 22.5 (1C), 24.8 (1C),
33.9 (1C), 54.9 (1C), 81.5 (1C), 164.3 (1C). 177.8 (1C); ESI-MS:
4.2.2.3. (5S)-5-(N-Trimethylacetamide-5-yl)-2,2,3-trimethyl-
imidazolidin-4-one 11. To a mixture of methyl-(2S)-2-amino-N1-
methyl-N4-tritylsuccinamide 10 (4.48 g; 11.6 mmol) in 35 mL dry
methanol were added acetone (7 mL; 5.5 g; 95 mmol) and
p-TsOH (0.10 g; 0.59 mmol). The resulting mixture was stirred at
m/z calcd for C8H14N6O: 210; found 211 [M+H]+, ½a D23
¼ ꢂ72:2
ꢁ
(c 1.0, MeOH).

1876
A. Hartikka et al. / Tetrahedron: Asymmetry 20 (2009) 1871–1876
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Lemay, M.; Ogilvie, W. W. Org. Lett. 2005, 7, 4141; (d) Sakakura, A.; Suzuki, K.;
Nakano, K.; Ishihara, K. Org. Lett. 2006, 8, 2229; (e) Kano, T.; Tanaka, Y.;
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Synth. Catal. 2006, 348, 2457; (g) Lemay, M.; Ogilvie, W. W. J. Org .Chem. 2006,
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4.2.2.7. (5S)-5-((1H-Tetrazole-5-yl)methyl)-2,2,3-trimethyl-imi-
dazolidin-4-one hydrochloric acid salt 14a. (5S)-5-((1H-Tetra-
zole-5-yl)methyl)-2,2,3-trimethyl-imidazolidin-4-one 14 (200 mg;
0.95 mmol) was converted to the corresponding hydrochloric acid
salt by the addition of a solution of 2 M HCl in MeOH (1.9 mL;
3.8 mmol) followed by dry diethyl ether (10 mL). The homoge-
neous solution became turbid, and a precipitate formed. The
heterogeneous solution was concentrated under reduced pressure
to give the title compound as a white solid, which was directly
dissolved in CH3OH/H2O (95/5 v/v) to provide the 1 M catalyst
solution used in the reactions.
Acknowledgments
We are grateful to Vetenskapsrådet (The Swedish Research
Council) for financial support, the Swedish Institute (SI) for a schol-
arship to LH, and the Foundation Olle Engkvist Byggmästare for a
scholarship to PPB.
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