A new chiral lithium amide based on (S)-2-[1-(3,3- dimethyl)pyrrolidinylmethyl]pyrrolidine-synthesis, NMR studies and use in the enantioselective deprotonation of cyclohexene oxide

Article abstract of DOI:10.1016/S0957-4166(98)00085-8

A new chiral lithium amide has been designed starting from (S)-proline. This new chiral lithium amide has been used for asymmetric deprotonation/ring opening of cyclohexene oxide to give (S)-2-cyclohexen-1-ol in 88% yield and 78% enantiomeric excess. NMR studies of the lithium amide and the ligand- substrate complex are also presented.

Full text of DOI:10.1016/S0957-4166(98)00085-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1223–1229
A new chiral lithium amide based on (S)-2-[1-(3,3-
dimethyl)pyrrolidinylmethyl]pyrrolidine— synthesis, NMR
studies and use in the enantioselective deprotonation of
cyclohexene oxide
Agha Zul-Qarnain Khan«,† Rimke W. de Groot, Per I. Arvidsson and Öjvind Davidsson«, ∗
Department of Chemistry, Göteborg University, S-412 96, Göteborg, Sweden
Received 4 February 1998; accepted 24 February 1998
Abstract
A new chiral lithium amide has been designed starting from (S)-proline. This new chiral lithium amide has
been used for asymmetric deprotonation/ring opening of cyclohexene oxide to give (S)-2-cyclohexen-1-ol in 88%
yield and 78% enantiomeric excess. NMR studies of the lithium amide and the ligand–substrate complex are also
presented. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
The enantioselective deprotonation of epoxides to allylic alcohols by chiral lithium amides have
received much attention.1–4 The resulting allylic alcohols are usually obtained in high enantiomeric
excess (ee) and yield. Allylic alcohols of high enantiomeric purity are prospective starting materials
for many drugs and natural products.5–8 Most chiral lithium amides reported in the literature have
been used either as deprotonating reagents and/or chiral ligands in lithiation reactions.9,10 The most
studied reagents are perhaps those obtained from (S)-proline and/or containing pyrrolidine rings. With
the use of lithium (S)-2-(1-pyrrolidinylmethyl)pyrrolidide 1 in THF as solvent, cyclohexene oxide 2
has been enantioselectively deprotonated to give (S)-2-cyclohexen-1-ol (S)-3 in 84% yield and 80% ee
(Scheme 1).11–15 Recently we also reported the solvent induced isomerisation of 2-cyclohexen-1-ol to
3-cyclohexene-1-ol when the reaction was performed in 2,5-dimethyltetrahydrofuran under otherwise
similar conditions.16
∗
†
Corresponding author. E-mail: Ojvind.Davidsson@oc.chalmers.se
Present address: Organic Chemistry 2, Center for Chemistry and Chemical Engineering, Lund Institute of Technology, Lund
University, Box 124, S 221 00 Lund, Sweden.
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00085-8

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Scheme 1.
Attempts have been made to rationalise the stereochemical outcome of the deprotonation/ring opening
reaction by employing the proposed transition state structure of complexes between 1 and 2 (Fig. 1,
transition state complex A or B). It is believed that structure B, leading to product (S)-3, is responsible for
the high enantioselectivity due to less steric hindrance than structure A.4,12 However, concrete evidence
is still to be found.
Fig. 1. Proposed transition state structures for the enantioselective deprotonation of 2 by 1
We initiated NMR studies to obtain information about the solution state structure of 1 complexing 2 in
the hope that this would reflect a possible transition state structure responsible for the enantioselectivity
in the deprotonation/ring opening of 2. However, our attempts were hampered in the absence of any
suitable handles for the assignment of NMR signals in the overcrowded 1H NMR spectrum. To overcome
this problem without perturbing the demands of selectivity in the system, structural modifications
were made in the pyrrolidine moiety. Two methyl groups were introduced at the 3 position of (S)-2-
(1-pyrrolidinomethyl)pyrrolidine P-1 precursor to 1. From the NMR point of view, this new lithium
amide, lithium (S)-2-[1-(3,3-dimethyl)pyrrolidinylmethyl]pyrrolidide 4, contains the necessary handles
for signal assignment and thereby it can be used for structural studies in solution by NMR. Frequent
publications of new lithium amides in the literature17–20 has prompted us to report the synthesis and
efficiency of 4 in the enantioselective deprotonating of 2 and to present an account of the NMR solution
studies of the complex between 2 and 4.
2. Results and discussion
The precursor to 4, (S)-2-[1-(3,3-dimethyl)pyrrolidinylmethyl]pyrrolidine P-4 was synthesised by
following the general method reported in the literature for the synthesis of P-111–15 by coupling
3,3-dimethylpyrrolidine 621 with (S)-1-N-(benzyloxycarbonyl)proline 5 and following the other steps
according to Scheme 2.

A. Z.-Q. Khan et al. / Tetrahedron: Asymmetry 9 (1998) 1223–1229
1225
Scheme 2.
2.1. Enantioselective deprotonating efficiency of 4
The enantioselective deprotonating efficiency of 4 was tested by performing the reaction with 2 in THF.
Compound (S)-3 was obtained in 88% yield (isolated) (GC yield >99%) and 78% ee. This compares to
84% yield (isolated) (GC yield >99%) and 80% ee when 1 was used under otherwise similar reaction
conditions.
2.2. NMR studies
1
1
6
In order to determine the solution structure of 4, H–1H-COSY, H–1H-NOESY and Li NMR
1
experiments were performed. The H NMR spectra (CDCl3 and THF-d8) of the precursor P-4 gave a
singlet for the 30-methyls at the pyrrolidine rings at δ 1.04 despite the fact that the molecule possesses a
stereogenic carbon (two singlets were expected). This shows that there is no rotational restriction between
the two pyrrolidine moieties i.e. there is free rotation around the C(6)–N bond. However, the H NMR of
1
the corresponding amide 4 at −10°C in THF-d8 showed two separate 30-methyl proton NMR signals at
δ 1.05 and δ 1.12 indicating an element of rigidity in the structure due to a coordination of the lithium
cation with both of the nitrogen atoms leaving two free places for the solvent or substrate molecule to
occupy (Fig. 2). At 25°C these two 30-methylproton signals coalesce into one 30-methyl proton signal at
δ 1.10.
Fig. 2. The proposed structure of 4 monomer in THF. The NOE between H(2) and H(50,50) are shown
1
1
The H–1H-DQCOSY (optimised for H–C–C–H couplings) and H–1H-NOESY experiments were
performed to assign the two H(20,20) signals in the proton spectra. The two H(20,20) signals were used
as a starting point for the assignment of the 3D structure of 4 using NOEs. One of the H(20,20) protons
at δ 2.17 shows a NOE effect with one of the 30-methyl group proton signals at δ 1.05 whereas the other
H(20,20) proton at δ 2.55 shows a NOE effect with one of the 30-methyl group proton signals at δ 1.12
instead. In the case of H(40,40) protons, the proton appearing at δ 1.51 showed a correlation with the 30-

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Table 1
1 H NMR chemical shifts of 4 in THF-d8 at −10°C. The chemical shifts are arranged in two groups
for each face of 4, i.e. all the chemical shifts in the same column as H(2) are on the same side as H(2)
in 4
methylgroup protons at δ 1.05 while the other H(40,40) proton appearing at δ 1.65 showed NOE effects
with the 30-methylgroup protons at δ 1.12. With the help of COSY and NOESY NMR experiments we
were able to assign all the proton signals in the 3,3-dimethylpyrrolidine ring, see Table 1, Fig. 3.
Fig. 3. A 1H–1H-NOESY of 4 in THF-d8 at −10°C. The protons that appear on the same face as H(2) are emboldened in the
top proton NMR spectra
The orientation of two methyl groups at C(30) (axial or equatorial) was determined by looking for
NOE effects between H(2) at δ 3.45 of the (S)-proline ring and the H(6,6) at δ 1.83 and δ 2.48 in the
methylene bridge and H(20,20)–H(6,6), H(50,50)–H(6,6) NOEs, respectively. A NOE effect between H(2)
at δ 3.45 of the (S)-proline ring and H(50,50) at δ 2.17 and δ 3.23 of the pyrrolidine was observed (Fig. 2).
On the basis of these observations, it can be interpreted that the methyl groups are pointing as shown in
Fig. 2. It should be remembered that there is no rotation around the C(6)–N bond. The evidence of a
locked structure was confirmed by the absence of cross peaks due to NOE’s exchange, all the cross peaks
observed showed opposite intensity compared to the diagonal peaks.22
On addition of 2 to 4, a NOESY experiment of the complex was recorded at −10°C in THF-
d8. Cyclohexene oxide protons, appearing at δ 1.20, 1.37, 1.74, 1.79 and 3.11, showed weak NOE
correlations with the H(2,20,4,5 and 6) protons in 4. The NOE correlations between cyclohexene oxide
and 4 are most pronounced for the pyrrolidide ring. However, we hasten to add that the observable

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1227
NOE only gives an average picture of the cyclohexene oxide·4 complex in solution. The observed
NOE correlations between cyclohexene oxide and 4 are in good agreement with results obtained for
the deprotonation reaction of the cyclohexene oxide using analogues of the Asami reagent substituted at
the pyrrolidinyl and pyrrolidide ring moieties. Substitutions at the pyrrolidinyl ring had no or opposite
effect upon the ee in the above reaction.12,15 However, substitution at the pyrrolidide ring resulted in
a slight increase of the ee18 These observations are in accordance with the observed NOE correlations
described above.
3. Experimental
3.1. General
Glassware and syringes used for NMR and deprotonation reactions were dried at 50°C in a vacuum
oven before transfer into a glove box (Mecaplex GB 80 equipped with a gas purification system that
removes oxygen and moisture) containing a nitrogen atmosphere. Typical moisture content was less than
0.5 ppm. All manipulations concerning the deprotonation reactions were carried out in the glove box
using gas-tight syringes. Etheral solvents, distilled under nitrogen from sodium and benzophenone, were
kept over 4 Å molecular sieves in a septum sealed flask inside the glove box.
NMR spectra were recorded on a Varian Unity 400 MHz (1D spectra) or a Varian Unity 500 MHz
(2D spectra) machine. Mass spectral analysis was done on a VG Analytical ZabSpec sector instrument.
Chromatographic analyses were carried out using a Varian Star 3400 CX gas chromatograph using
a chiral stationary phase column (heptakis (6-O-methyl-2,3-di-O-pentyl)-cyclodextrin).23 All analyses
were done at 85°C (injector 225°C, detector 250°C) using He (2 ml/min.) as a carrier gas. (S)-
2-(1-Pyrrolidinylmethyl)pyrrolidine P-1 used for comparison was synthesised according to literature
methods.11–15
3.2. Preparation of (S)-3,3-dimethyl-1-[N-(benzyloxycarbonyl)prolyl]pyrrolidine 7
Dicyclohexylcarbodiimide (DCC, 2.92 g, 14.1 mmol) in 5 mL of CH2Cl2 was added to a solution of
(S)-N-(benzyloxycarbonyl)proline 5 (3.52 g, 14.1 mmol) in 10 mL of CH2Cl2. After stirring the mixture
for 30 min at 0°C, 3,3-dimethylpyrrolidine 621 (1.4 g, 14.1 mmol) dissolved in 10 mL CH2Cl2 was
added dropwise. The reaction temperature was then allowed to rise to room temperature and the mixture
was stirred for 68 h. At the end of reaction (monitored by TLC on silica gel; eluent EtOAc:MeOH
4:1; Rf 0.5) the precipitate was filtered off. The slightly yellow CH2Cl2 layer was washed with 2%
aqueous HCl solution (20 mL), 4% aqueous NaHCO3 solution (20 mL), water (20 mL) and brine (20
mL) before drying over anhydrous Na2SO4. Filtration and evaporation of the solvent gave a pale yellow
oil (3.9 g). The crude product was purified by flash chromatography on TLC grade silica gel using
EtOAc:hexane (9:1) as an eluent (Rf 0.25) and increasing the solvent polarity with MeOH. Yield 2.4 g
(52%); recrystallized from EtOAc:hexane (1:1); mp, 65–68°C; GC–(EI)MS: 330 (M+, 17), 204 (62), 195
(11), 160 (86), 126 (6), 98 (52), 91 (100), 83 (6), 69 (7), 55 (9), 44 (19); HRMS: M+ (found) 330.1924,
1
calcd for C19H26N2O3=330.1943; [α]D20=−6.70 (c=2.03, EtOH); H NMR (CDCl3): δ 0.88 (m, 6H),
1.43–2.16 (m, 6H), 3.14–3.70 (m, 6H), 4.36–4.54 (m, 1H), 5.02–5.21 (m, 2H), 7.30–7.40 (m, 5H) ppm;
13C NMR (CDCl3): δ 24.63, 26.09, 26.24, 29.74, 37.52, 39.77, 47.42, 58.18, 58.39, 58.3, 67.06, 128–137,
154.5, 155.5, 171.5 and 171.9 ppm.

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3.3. Preparation of (S)-2-[1-(3,3-dimethyl)pyrrolidinylmethyl]pyrrolidine P-4
Pd/C catalyst (10%, 69 mg) was added to solution of (S)-3,3-dimethyl-1-[N-
a
(benzyloxycarbonyl)prolyl]pyrrolidine 7 (1.55 g, 4.69 mmol) in 20 mL of dry methanol, and the
mixture hydrogenated in a PARR-apparatus for 24 h. After removal of the catalyst by filtration over
Celite, and the methanol by rotary evaporator, 960 mg of crude 8 was obtained as an oil. Both TLC and
NMR indicated the desired product that was used in the next step without purification.
To a suspension of LiAlH4 (0.9 g, 24 mmol) in 100 mL of dry THF cooled to 0°C and kept under a
nitrogen atmosphere, was dropwise added crude 8 dissolved in 10 mL THF. The mixture was refluxed for
20 h and monitored by TLC. When the reaction was complete 2 mL of saturated Na2SO4 solution was
carefully added. The solution was filtered under suction and THF removed on a rotary evaporator. The
product was stripped twice with dry toluene to remove traces of water. The crude P-4 as oil was purified
by bulb-to-bulb distillation (bp 100°C/0.5 mbar) and obtained as a colourless oil. Yield 50% (430 mg,
2.36 mmol); GC–MS (CI): 183 (M+1, 7), 131 (10), 119 (6) 112 (100); HRMS: (M+1) found: 183.1857,
calcd for C11H22N2: 183.1861; [α]D21=+14.2 (c=2.62, EtOH); 1H NMR (CDCl3): δ 1.04 (s, 6H), 1.30
(m, 1H), 1.52 (t, 2H), 1.69 (m, 2H), 1.82 (m, 1H), 2.23–2.28 (2H), 2.34–2.44 (2H), 2.57 (m, 2H), 2.82
(m, 1H), 2.93 (m, 1H), 3.14 (m, 1H) ppm; 13C NMR (CDCl3): δ 25.16 (CH2), 29.75 (CH3), 30.07 (CH2),
37.70 (C(CH3)2), 39.82 (CH2), 46.18 (CH2), 54.90 (CH2), 57.29 (CH), 62.26 (CH2), 68.88 (CH2) ppm;
UV (EtOH): 285 (2100).
3.4. Enantioselective deprotonation of 2 with 1 or 4
To an ice cooled solution of diamine precursor (0.61 mmol) in 2 mL of THF was added 0.61 mmol
of n-BuLi (1.7 M in hexane). The reaction mixture was kept at 0°C for 30 minutes. Cyclohexene oxide
2 (0.51 mmol) was added and reaction mixture was allowed to reach ambient temperature. At intervals,
10 mL of the sample was withdrawn and the reaction was quenched with 100 mL of sat. ammonium
chloride solution, diluted with DEE, neutralised with 0.5 M HCl, washed with brine and water and dried
over anhydrous sodium sulphate. The mixture was then analysed by GC with a chiral stationary phase
column.
Acknowledgements
Special thanks to Professor Per Ahlberg for guidance and to the Swedish Natural Science Research
Council for the award of post-doctoral fellowship to AZK. Rimke W de Groot was an ERASMUS student
from Groningen University, The Netherlands.
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