Synthesis of a silanol-substituted proline analog as organocatalyst

Article abstract of DOI:10.1515/znb-2009-1009

A proline-derived silanol, was designed as a novel potential organocatalyst, and synthesized starting from the tetrazole 3. The central idea was the combination of an acidic (tetrazole) and a basic functionality (pyrrolidine) with a silanol moiety in the

Full text of DOI:10.1515/znb-2009-1009

Synthesis of a Silanol-substituted Proline Analog as Organocatalyst
Daniel Krachta, Susumu Saitob, Roland Fro¨hlichc, and Bernhard Wu¨nscha
a Institut fu¨r Pharmazeutische und Medizinische Chemie der Universita¨t Mu¨nster,
Hittorfstraße 58 – 62, 48149 Mu¨nster, Germany
b Department of Chemistry, Graduate School of Science, Nagoya University, Furo, Chikusa,
Nagoya 464-8602, Japan
c Organisch-Chemisches Institut der Westfa¨lischen Wilhelms-Universita¨t Mu¨nster, Corrensstraße 40,
48149 Mu¨nster, Germany
Reprint requests to Prof. Dr. B. Wu¨nsch. Fax: +49-251-8332144. E-mail: wuensch@uni-muenster.de
Z. Naturforsch. 2009, 64b, 1169 – 1175; received July 14, 2009
A proline-derived silanol, was designed as a novel potential organocatalyst, and synthesized start-
ing from the tetrazole 3. The central idea was the combination of an acidic (tetrazole) and a basic
functionality (pyrrolidine) with a silanol moiety in the same molecule. The synthesis of 7 was per-
formed in four reaction steps starting with the tetrazole 3. In the solid state (X-ray crystal structure
analysis) the crucial functional groups show a favorable orientation. A chiral HPLC method and a
chiral capillary electrophoresis method have been established for the investigation of the kinetic res-
olution of the racemic alcohols 9 and 11. Acetylation reactions of alcohols were not accelerated by
the organocatalyst 7, and the produced ee values were rather low.
Key words: Proline-derived Tetrazole, Silanol, Organocatalyst, Kinetic Resolution of Alcohols,
Chiral HPLC, Chiral Capillary Electrophoresis
Introduction
Catalysts employed for enantioselective syntheses
of organic compounds, e. g. pharmaceutical products,
agrochemicals, or fine chemicals, generally fall into
three categories: transition metal complexes, enzymes
and organocatalysts. Organocatalysts represent small
organic molecules, which are able to catalyze a par-
ticular organic reaction. In contrast to transition metal
complexes, the catalytic activity of organocatalysts re-
sides in the low molecular weight organic molecule
itself. Usually, organocatalysts are inexpensive, non-
toxic and, in comparison with enzymes, stable under
most reaction conditions and readily available in both
enantiomeric forms [1].
Fig. 1. The organocatalyst (S)-proline (1) compared with the
designed silanol-modified derivatives 2.
alysts represents an interesting strategy of accessing
enantiomerically pure compounds [8]. The idea of this
project was the combination of the crucial basic and
acid functional groups of the proline system (1) with a
silanol moiety [9] in the same molecule (2) to get a new
type of catalyst for enantioselective acylation reactions
(Fig. 1).
Proline belongs to the most widely used organocat-
alysts in chemistry, because it is able to catalyze
intermolecular Michael additions [2], Mannich reac-
tions [3], inter- [4] and intramolecular aldol reac-
tions [5], and addition reactions on N=N [6] and N=O
Results ans Discussion
The silanol moiety was expected to bind the acylat-
double bonds [7]. (R)-and (S)-proline are both com- ing agent, i. e. the acetyl group transferred from acetic
mercially available in bulk quantities and thus repre- anhydride or an enol acetate. Thereby one enantiomer
sent particularly attractive amino acid organocatalysts. of a racemic alcohol should be preferably fixed and ac-
In the field of enantioselective syntheses the ki- tivated by two hydrogen bonds to the acidic and basic
netic resolution of secondary alcohols using organocat- functional groups of the catalyst. The high order of this
c
0932–0776 / 09 / 1000–1169 $ 06.00 ꢀ 2009 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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1170
D. Kracht et al. · Synthesis of a Silanol-substituted Proline Analog as Organocatalyst
Fig. 2. Postulated catalytic mecha-
nism of the designed organocatalyst 7
during acetylation of racemic alco-
hols.
Scheme 1. Reagents and reaction
conditions: (a) 2-Bromobenzalde-
hyde, NaBH(OAc)3, THF, 2 h, r. t.,
88 %; (b) Ph3CCl, NEt3, T◦HF, 2 h,
r. t., 93 %; (c) n-BuLi, −78 C, THF,
◦
30 min, −78 C, then Ph2Si(OEt)2,
2 h, −78 ◦C, 36 h, r. t., (d) HCl, 14 h,
r. t., 35 %.
intermediate complex should result in a kinetic resolu- action with diethoxydiphenylsilane provided the silyl
tion of the racemic alcohol, i. e. one enantiomer should ether 6, which was hydrolyzed without isolation with
be acetylated much faster than the other enantiomer, diluted HCl to give the triarylsilanol 7 (Scheme 1).
which should thus be left unchanged (Fig. 2).
Recrystallization of the proline-derived silanol 7
from a mixture of cyclohexane and CH2Cl2 pro-
vided crystals, which were suitable for an X-ray crys-
tal structure analysis. The structure shown in Fig. 3
clearly demonstrates that the three important func-
tional groups, the silanol moiety, the basic pyrrolidine
N atom and the acidic tetrazole proton, have a favor-
able orientation, which is an ideal condition for the
enantioselective acetyl group transfer.
The synthesis of the silanol-modified proline ana-
log 7 started with the tetrazole 3, which is avail-
able from the natural amino acid (S)-proline (1) in
five reaction steps [10]. Reductive alkylation of the
secondary amine 3 with 2-bromobenzaldehyde and
NaBH(OAc)3 [11] led to the bromobenzyl derivative 4
in 88 % yield. Since a halogen-metal exchange was
planned for the introduction of the silanol moiety, the
tetrazole system of 4 was protected with trityl chloride
For purpose of comparison the tetrazolylpyrroli-
to give the trityl derivative 5 in 94 % yield. Halogen- dine 8 bearing only a small methyl group instead of the
metal exchange with n-butyllithium and subsequent re- silanol moiety at the pyrrolidine N atom was synthe-
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D. Kracht et al. · Synthesis of a Silanol-substituted Proline Analog as Organocatalyst
Table 1. Kinetic resolution of racemic alcohol 9 using the organocatalysts 7 and 8.
1171
Entry
Catalyst, amount
–
Ac2O (equiv.)
NEt3 (equiv.)
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Temp. (◦C)
Time (h)
Conv. (%)
ee of 10 (%)
1
2
3
4
5
1
1
0.75
0.75
2
–
–
0.75
0.75
2
2
36
36
20
20
2
5
22
12
24
66
0
8
0
4
11
7, 5 mol-%
20
20
20
20
–
7, 5 mol-%
8, 5 mol-%
Fig. 4. Chiral HPLC analysis of racemic alcohol 9 and ac-
etate 10: Chiralcel AD-H, 5 µm, n-hexane/ethanol 99/1, flow
rate 1.0 mL min−1, UV detection at 220 nm.
Fig. 3. Molecular structure of one of the two crystallograph-
ically independent molecules of the organocatalyst 7 in the
solid state showing a favorable orientation of the three cru-
cial functional groups.
Some of the performed experiments are summarized
in Table 1. In the first control experiment, racemic
phenylethanol (9) was reacted with Ac2O in CH2Cl2
which resulted in very low conversion (5 %) and no dif-
ferentiation of the enantiomers (Table 1, entry 1). Ad-
dition of 5 mol-% of the organocatalyst 7 (entry 2) led
to an increase of the conversion by 22 % and a slight
enantiomeric excess of the formed acetate 10 (ee 8 %).
Whereas the reaction rate was increased upon addition
of NEt3, the enantiomeric excess of 10 was reduced
due to increased uncatalyzed background acetylation
(entries 3, 4). Acetylation of the alcohol 9 in the pres-
ence of the methylated proline derivative 8 resulted
in 66 % conversion with low enantiomeric excess of
the produced acetate 10 (ee 11 %, entry 5).
Since we are interested in bicyclic compounds as
novel κ-receptor agonists [13], the organocatalyst 7
was applied on the kinetic resolution of the bicyclic
endo-configurated alcohol 11 [13b]. The progress of
the acetylation was observed using a chiral capillary
electrophoresis method, which has been developed
starting with a reported method [14]. In Fig. 5 a typ-
ical electropherogram is shown. With hydroxypropyl-
β-cyclodextrin as chiral selector, the alcohol 11 and the
acetate 12 as well as their enantiomers were separated
in a single capillary electrophoresis run.
Scheme 2. Reagents and reaction conditions: (a) Formalin,
CH3OH, H2, 1 bar, Pd/C, r. t., 12 h, 84 %.
sized. The methylation of the secondary amine 3 was
performed under reductive conditions with formalde-
hyde and H2, Pd/C (Scheme 2).
With the new organocatalysts 7 and 8 in hand
their catalytic properties for the kinetic resolution
were investigated with the standard racemic alcohol
1-phenylethanol (9). Within this project a novel chi-
ral HPLC method was developed, which allows the si-
multaneous separation of both pairs of enantiomers in
a single run. Thus the ratio of enantiomers of the alco-
hol 9 and the acetate 10 as well as the conversion can
be directly determined (Fig. 4). In this method the chi-
R
ral stationary phase Chiralcel AD-Hꢀ containing mod-
ified amylose as chiral selector, and the mobile phase
n-hexane/ethanol were used [12].
As shown for the prototypical phenylethanol (9),
the acetylation rate of the conformationally more con-
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1172
D. Kracht et al. · Synthesis of a Silanol-substituted Proline Analog as Organocatalyst
Table 2. Kinetic resolution of racemic alcohol 11 using the organocatalysts 7 and 8.
Entry
Catalyst, amount
–
7, 10 mol-%
8, 10 mol-%
Ac2O (equiv.)
NEt3 (equiv.)
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
Temp. (◦C)
Time (h)
Conv. (%)
ee of 12 (%)
1
2
3
2
2
2
2
2
2
20
20
20
36
36
36
5
8
11
0
3.8
4.5
Fig. 5. Chiral CE analysis of racemic al-
cohol 11 and acetate 12: Hydroxyprop-
yl-β-cyclodextrin, 0.1 M phosphoric
acid pH = 2.0, hydrodynamic injection
for 5 s at 0.5 psi.
strained bicyclic alcohol 11 was only slightly increased Experimental Section
by the organocatalyst 7 (see Table 2, entries 1 and 2).
Moreover, the differentiation of the enantiomeric al-
cohols was negligible. Using the methylated deriva-
tive 8 as organocatalyst led to a similar observation
(entry 3).
General marks
Unless otherwise noted, moisture-sensitive reactions
were conducted under dry nitrogen. THF was dried with
sodium/benzophenone and was freshly distilled before use.
Thin layer chromatography (tlc): Silica gel 60 F254 plates
(Merck). Flash chromatography (fc): Silica gel 60, 40 –
64 µm (Merck); parentheses include: diameter of the col-
umn, height of SiO2 column, fraction size, eluent, Rf value.
Melting point: Melting point apparatus SMP 3 (Stuart Scien-
tific), uncorrected. Optical rotation: Polarimeter 341 (Perkin
Elmer); 1.0 dm tube; concentration c in g/100 mL, op-
tical rotation [α] in grad mL dm−1 g−1. MS: MAT GCQ
(Thermo-Finnigan); EI = electron impact, ESI = electrospray
ionization. IR: IR spectrophotometer 480Plus FT-ATR-IR
(Jasco). 1H NMR (400 MHz), 13C NMR (100 MHz):
Mercury-400BB spectrometer (Varian); δ in ppm rela-
tive to tetramethylsilane; coupling constants J are given
with 0.5 Hz resolution. HPLC: Merck Hitachi Equipment;
UV detector: L-7400; autosampler: L-7200; pump: L-7100;
In conclusion, the synthesis of a novel potential
organocatalyst derived from the proteinogenic amino
acid (S)-proline is described. In the organocatalyst 7
the carboxylic acid moiety of proline is replaced by
an acidic tetrazole system, and a silanol moiety is
introduced into the N substituent. The X-ray crys-
tal structure analysis of 7 shows a favorable orienta-
tion of the crucial functional groups. A novel chiral
R
HPLC method (Chiralcel AD-Hꢀ) and a novel chi-
ral capillary electrophoresis method (hydroxypropyl-
β-cyclodextrin) were established to observe the ki-
netic resolution of racemic alcohols. Unfortunately,
the reaction rate was not increased considerably by
the designed organocatalyst 7. Furthermore, the enan-
tiomeric excess of the produced acetates 10 and 12 was
rather low. The organocatalyst 8 with the small methyl
group led to the same result indicating that the silanol
moiety does not influence the enantioselective acetyla-
tion of secondary alcohols. In future work the catalytic
activity of 7 in further reactions will be investigated.
R
degasser: L-7614; column: LiChrospherꢀ 60 RP-select B
(5 µm), 250 – 4 mm; flow rate: 1.00 mL min−1; injec-
tion volume: 5.0 µL; detection at λ = 210 nm; solvents:
A: water with 0.05 % (v/v) trifluoroacetic acid; B: acetoni-
trile with 0.05 % (v/v) trifluoroacetic acid; gradient elution:
(A %): 0 min: 90 %, 4 min: 90 %, 29 min: 0 %, 31 min: 0 %,
31.5 min: 90 %, 40 min: 90 %.
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D. Kracht et al. · Synthesis of a Silanol-substituted Proline Analog as Organocatalyst
1173
(S)-5-[1-(2-Bromobenzyl)pyrrolidin-2-yl]-1H-tetrazole (4)
Diphenyl-{2-[(S)-2-(1H-tetrazol-5-yl)pyrrolidin-1-
ylmethyl]phenyl}silanol (7)
Under Ar atmosphere, NaBH(OAc)3 (318 mg, 1.5 mmol)
was added to a solution of 3 (139 mg, 1.0 mmol) and 2-
bromobenzaldehyde (175 µL, 1.5 mmol) in THF (10 mL).
The reaction mixture was stirred at r. t. for 2 h. Then the
solvent of the reaction mixture was removed in vacuo.
The residue was purified by fc [3 cm, 15 cm, 10 mL,
CH2Cl2/MeOH 9.5/0.5 → 9/1, Rf = 0.39 (CH2Cl2/MeOH
9/1)] to afford 272 mg (88 %) of 4 as a colorless solid,
m. p. 181 ◦C. – C12H14BrN5 (Mr = 308.2). – 1H NMR
(CDCl3): δ = 1.89 – 2.00 (m, 2H, CH2CH2), 2.01 – 2.13 (m,
1H, CH2CH2), 2.38– 2.50 (m, 1H, CH2CH2), 2.78 (dd, J =
17.2/9.4 Hz, 1H, NCH2), 3.43 – 3.52 (m, 1H, NCH2), 3.88
(d, J = 13.3 Hz, 1H, PhCH2N), 4.03 (d, J = 13.3 Hz, 1H,
PhCH2N), 4.45 (dd, J = 8.6/6.3 Hz, 1H, NCH), 6.57 (s
broad, 1H, tetrazole-H), 7.11 (td, J = 7.8/1.6 Hz, 1H, 4ꢀ-
Hphenyl or 5ꢀ-Hphenyl), 7.20 (td, J = 7.8/1.6 Hz, 1H, 4ꢀ-
Hphenyl or 5ꢀ-Hphenyl), 7.31 (dd, J = 7.8/1.6 Hz, 1H, 6ꢀ-
Hphenyl), 7.51 (dd, J = 7.8/1.6 Hz, 1H, 3ꢀ-Hphenyl). – IR
(neat): ν (cm−1) = 1473, 1444 and 1422 (m, N=N, C=N and
C–H), 754 (s, arom. out of plane). – MS (EI): m/z (%) =
307 (5) [M, 79Br]+, 309 (6) [M, 81Br]+, 237 (64) [M–
Under N2, 5 (235 mg, 1.1 mmol) was dissolved in THF
(20 mL), and the solution was cooled to −78 ◦C. Then
a 1.6 M solution of n-butyllithium in n-hexane (690 µL,
1.1 mmol) was added slowly. The reaction mixture was
◦
stirred for 30 min at −78 C. Then diphenyldiethoxysilane
(400 µL, 1.5 mmol) was added dropwise. After stirring
at −78 ◦C for 2 h, the mixture was allowed to warm to r. t. Af-
ter 36 h (product 6) 1 M aqueous HCl (10 mL) was added, and
the resulting mixture was stirred at r. t. for additional 14 h.
Then pH = 7 was adjusted by addition of 0.5 M aqueous
NaOH, and the reaction mixture was extracted with CH2Cl2
(3×). The combined organic layers were dried (Na2SO4) and
filtered, and the solvent was removed in vacuo. The residue
was purified by fc [4 cm, 15 cm, 20 mL, CH2Cl2/MeOH
9.5/0.5 → 9/1, Rf = 0.38 (CH2Cl2/MeOH 9/1)] to afford
149 mg (35 %) of 7 as a colorless solid, m. p. 212 ◦C. –
C24H25N5OSi (Mr = 427.6). – 1H NMR (CDCl3): δ = 1.74 –
1.86 (m, 2H, CH2CH2), 1.98 – 2.10 (m, 1H, CH2CH2), 2.22 –
2.34 (m, 1H, CH2CH2), 2.55 (dd, J = 18.8/8.6 Hz, 1H,
NCH2), 2.96 – 3.06 (m, 1H, NCH2), 3.58 (d, J = 12.5 Hz,
1H, PhCH2N), 3.93 (d, J = 12.5 Hz, 1H, PhCH2N), 4.37 (t,
J = 7.8 Hz, 1H, NCH), 7.15 – 7.40 (m, 12H, arom. H), 7.50
(d, J = 6.3 Hz, 2H, arom. H). The signals for the tetrazole-H
and the SiOH could not be detected. – IR (neat): ν (cm−1) =
1457, 1427 and 1445 (m, N=N, C=N and C–H), 763, 739
and 699 (m, arom. out of plane). – MS (ESI): m/z (%) =
tetrazole, 79Br]+, 239 (63) [M–tetrazole, 81Br]+. – [α]2D0
=
−16.4 (c = 0.59; MeOH). – HPLC: tR = 11.1 min, pu-
rity 99.6 %.
(S)-5-[1-(2-Bromobenzyl)pyrrolidin-2-yl]-1-trityl-1H-
tetrazole (5)
428 (100) [M + H]+, 877 (21) [2M + Na]+. – [α]20
=
D
+17.5 (c = 0.48; CH2Cl2). – HPLC: tR = 18.9 min, pu-
Trityl chloride (257 mg, 0.92 mmol) was added to a so-
lution of 4 (260 mg, 0.84 mmol) and triethylamine (350 µL,
2.5 mmol) in THF (10 mL). The reaction mixture was stirred
at r. t. for 2 h, and filtered, and the solvent removed in
vacuo. The residue was purified by fc (4 cm, 15 cm, 15 mL,
n-hexane/ethyl acetate 9/1, Rf = 0.38) to afford 431 mg
(93 %) of 5 as a colorless solid, m. p. 152 ◦C. – C31H28BrN5
rity 100 %.
(S)-5-(1-Methylpyrrolidin-2-yl)-1H-tetrazole (8)
Aqueous formaldehyde (40 %, 415 µL, 6.0 mmol) was
added to a solution of 3 (417 mg, 3.0 mmol) in methanol
(10 mL). Then 10 % Pd/C (200 mg) was added, and the
resulting mixture was stirred under an H2 atmosphere at
r. t. for 12 h. The reaction mixture was filtered through
1
(Mr = 550.5). – H NMR (CDCl3): δ = 1.81 – 1.92 (m, 1H,
CH2CH2), 1.96 – 2.08 (m, 1H, CH2CH2), 2.18– 2.33 (m,
2H, CH2CH2), 2.51 (dd, J = 17.2/8.6 Hz, 1H, NCH2), 3.05
(ddd, J = 11.7/8.6/3.1 Hz, 1H, NCH2), 3.58 (d, J = 14.1 Hz,
1H, PhCH2N), 3.78 (d, J = 14.1 Hz, 1H, PhCH2N), 4.12
(t, J = 7.0 Hz, 1H, NCH), 7.01 (td, J = 7.8/1.6 Hz, 1H,
4ꢀ-Hphenyl or 5ꢀ-Hphenyl), 7.05 – 7.10 (m, 6H, Htrityl), 7.15 (td,
J = 7.8/1.6 Hz, 1H, 4ꢀ-Hphenyl or 5ꢀ-Hphenyl), 7.24 – 7.36 (m,
10H, 6ꢀ-Hphenyl and Htrityl), 7.44 (dd, J = 7.8/1.6 Hz, 1H,
R
Celiteꢀ, and the filtrate was concentrated in vacuo. Ad-
dition of Et2O led to a precipitate which was recrystal-
lized from MeOH/Et2O to afford 386 mg (84 %) of 8 as
colorless solid, m. p. 225 ◦C. – C6H11N5 (Mr = 153.2). –
1H NMR (CD3OD): δ = 2.23 – 2.33 (m, 2H, CH2CH2),
2.38 – 2.57 (m, 2H, CH2CH2), 2.80 (s, 3H, NCH3), 3.22 –
3ꢀ-Hphenyl). – IR (neat): ν (cm−1) = 1492, 1467 and 1445 3.30 (m, 1H, NCH2), 3.58 – 3.68 (m, 1H, NCH2), 4.66
(m, N=N, C=N and C–H), 757, 746 and 697 (m, arom. out (t, J = 8.6 Hz, 1H, NCH). A signal for the tetrazole
of plane). – MS (ESI): m/z (%) = 1125 (48) [2M + Na, 2x H atom could not be detected. – IR (neat): ν (cm−1) =
81Br]+, 1123 (86) [2M + Na, 79Br/81Br]+, 1121 (45) [2M 2962 (w, C–H), 1458, 1430 and 1417 (m, N=N, C=N
+ Na, 2x 79Br]+, 552 (49) [M + H, 81Br]+, 550 (50) [M + and C–H). – MS (EI): m/z (%) = 153 (98) [M, 3]+,
H, 79Br]+, 243 (100) [CPh3]+. – [α]D20 = −33.9 (c = 0.59; 84 (98) [M–tetrazole]+. – [α]2D0 = −28.7 (c = 0.58;
CH2Cl2).
MeOH).
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1174
D. Kracht et al. · Synthesis of a Silanol-substituted Proline Analog as Organocatalyst
(1RS,5SR,6RS)-4-Tosyl-1,4-diazabicyclo[3.3.1]nonan-6-yl
acetate (12)
General procedure for the catalytic kinetic resolution of
racemic 1-phenylethanol
Acetic anhydride (150 µL, 1.6 mmol) was added to a so-
lution of ( )-1-phenylethanol (100 µL, 0.8 mmol) and the
respective catalyst candidate 7 or 8 (5 mol-% = 0.04 mmol) in
CH2Cl2 (5 mL). When tlc control showed an adequate con-
version, the reaction was stopped by the addition of a satu-
rated solution of NaHCO3 (10 mL). The organic layer was
separated, dried (Na2SO4) and filtered, and the solvent was
removed in vacuo. The crude product was dissolved in 2 mL
of cyclohexane/ethyl acetate [2/1]. In order to remove the
catalyst from the reaction mixture, this solution was filtered
through a pad of silica gel, washed with cyclohexane/ethyl
acetate [2/1], and concentrated under reduced pressure. The
conversion and the enantiomeric excess were directly ana-
lyzed by a chiral HPLC method which separated the enan-
tiomers of both compounds in one HPLC experiment.
Under N2 atmosphere, acetic anhydride (140 µL,
1.50 mmol) was added to a solution of 11 [13b] (90 mg,
0.30 mmol), NEt3 (210 µL, 1.50 mmol) and DMAP (4 mg,
0.03 mmol) in CH2Cl2 (15 mL). After 2 h at r. t. a satu-
rated NaHCO3 solution was added. The organic layer was
separated, and the aqueous layer was extracted with CH2Cl2
(2 ×). The combined organic layers were dried (Na2SO4)
and filtered, and the solvent was removed in vacuo. The
residue was purified by fc [2 cm, 10 mL, CH2Cl2/MeOH
9.5/0.5, Rf = 0.26 (CH2Cl2/MeOH 9.5/0.5)] to afford
94 mg (92 %) of 11 as a colorless solid, m. p. 168 ◦C. –
C16H22N2O4S (Mr = 338.4). – 1H NMR (CDCl3): δ =
1.79 – 1.89 (m, 1H, 7-H), 1.93 – 2.04 (m, 1H, 7-H), 2.09 (s,
3H, O2CCH3), 2.40 (s, 3H, ArCH3), 2.76 – 2.84 (m, 2H,
NCH2), 2.88 (dd, J = 14.1/5.5 Hz, 1H, NCH2), 2.93 – 3.03
(m, 1H, NCH2), 3.04 – 3.08 (m, 2H, NCH2), 3.18 – 3.26 (m,
1H, NCH2), 3.50 – 3.60 (m, 1H, NCH2), 4.04 – 4.09 (m, 1H,
5-H), 4.95 (ddd, J = 11.7/7.0/3.9 Hz, 1H, 6-H), 7.26 (d, J =
7.8 Hz, 2H, 3ꢀ-Htosylate, 5ꢀ-Htosylate), 7.67 (d, J = 7.8 Hz, 2H,
2ꢀ-Htosylate, 6ꢀ-Htosylate). – IR (neat): ν (cm−1) = 1736 (s,
C=O), 1158 (s, S=O), 816 (m, arom. out of plane). – MS (EI):
m/z (%) = 338 (19) [M]+, 183 (100) [M–SO2C6H4CH3]+. –
HPLC: tR = 15.1 min, purity 99.7 %.
Separation of enantiomers by chiral HPLC
Equipment (all Merck-Hitachi): pump: L-6200A; UV de-
tector: L-7400; data transfer: 1 V interface of an A/D-
converter; data acquisition: HSM-Software; column: Chiral-
cel AD-H, 5 µm, ∅ 4.6 mm, 25 cm, Daicel Chemical Indus-
tries, Japan; mobile phase: n-hexane/ethanol 99/1 at a flow
rate of 1.0 mL/min; detection: UV absorption at 220 nm; re-
tention times t(R-10) = 5.0 and t(S-10) = 5.8 min, t(R-9) =
19.5 and t(S-9) = 21.4 min.
X-Ray crystal structure analysis of 7
Recrystallization of 7 from cyclohexane/CH2Cl2 gave
single crystals suitable for X-ray crystal structure analy-
sis. C24H25N5OSi, Mr = 427.58; crystal size 0.30 × 0.08 ×
General procedure for the catalytic kinetic resolution of the
racemic bicyclic alcohol 11
0.05 mm3; T = 223(2) K, CuKα radiation, λ = 1.54178 A;
Acetic anhydride (10 µL, 0.1 mmol) was added to a
solution of 11 [13b] (15 mg, 0.05 mmol), NEt3 (14 µL,
0.1 mmol) and the respective catalyst candidate 7 or 8
(10 mol-%) in CH2Cl2 (3 mL). The conversion was moni-
tored by tlc. After 36 h at r. t., 0.1 mL of the reaction mixture
was diluted with DMSO (2 mL). The resulting solution was
diluted with H3PO4 (0.1 M) to 5 mL. The conversion and the
enantiomeric excess were directly analyzed by a CE method,
which separated the enantiomers of the alcohol 11 and the
acetate 12 in one single CE experiment.
˚
monoclinic crystal system, space group P21 (no. 4); unit cell
˚
=
dimensions a = 9◦.5694(4), b = 15.0095(6), c = 16.1055(7) A,
3
˚
β = 102.251(2) , V = 2260.6(2) A , Z = 4, Dcalcd.
1.256 mg m−3, µ(CuKα ) = 11.17 cm−1, F(000) = 904 e;
θ range: 4.07 – 67.62◦, hkl range: 11, −15/+17, −18/+
19; reflections collected / unique: 17837 / 6920, Rint = 0.048,
completeness to θmax = 98.0 %; absorption correction: semi-
empirical from equivalents, Tmax / Tmin = 0.946 / 0.731; re-
finement: full-matrix least-squares on F2; data / restraints /
parameters: 6920 / 1 / 567; goodness-of-fit on F2 = 1.039; fi-
nal R indices [I ≥ 2(I)]: R1 = 0.041, wR2 = 0.104; R indices
(all data): R1 = 0.044, wR2 = 0.107; Flack parameter x =
CE method modified according to ref. [14]
CE apparatus: Beckman P/ACETM Capillary Elec-
trophoresis System; data acquisition: Beckman Carat-
software; capillary: bare fused-silica capillaries (effective
length 30 cm, total length 40 cm, diameter 50 µm); detection:
DAD detector at 190 nm; injection: hydrodynamic pressure
injection (5 s, 0.5 psi). The background electrolyte was pre-
pared from 0.1 M phosphoric acid adjusted to pH = 2.0 by
0.03(2); ∆ρfin (max / min) = 0.21 / −0.23 e A−3. Comments:
˚
Data were collected on a Nonius KappaCCD diffractome-
ter. Programs used: data collection COLLECT (Nonius B.V.,
1998), data reduction DENZO-SMN [15], absorption correc-
tion DENZO [16], structure solution SHELXS-97 [17], struc-
ture refinement SHELXL-97 [18], graphics SCHAKAL [19].
CCDC 739292 contains the supplementary crystallo- dropwise addition of NEt3. Hydroxypropyl-β-cyclodextrin
graphic data for this paper. These data can be obtained free was dissolved in this phosphate-NEt3 buffer at a concentra-
of charge via www.ccdc.cam.ac.uk/data request/cif.
tion of 0.65 mg/mL (0.45 mM). Prior to the injection of each
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D. Kracht et al. · Synthesis of a Silanol-substituted Proline Analog as Organocatalyst
1175
sample solution, the capillary was rinsed for 3 min with back- Acknowledgement
ground electrolyte. The samples were injected hydrodynam-
ically for 5 s at 0.5 psi. Separation was carried out by apply-
This work was performed within the International
Research Training Group “Complex Functional Systems in
Chemistry: Design, Synthesis and Applications” in collab-
oration with the University of Nagoya. Financial support
of this IRTG by the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
ing a voltage of 25 kV with normal polarity. The temperature
◦
of the capillary was kept at 20 C during the separation by
a liquid cooling system. After each run, the capillary was
rinsed with methanol for 2 min, water for 30 s, 0.1 M NaOH
for 2 min, and again water for 30 s.
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