Checked by Michael R. Reeder and Robert K. Boeckman, Jr..
1. Procedure
B.
(R)-(+)-2-(Diphenylhydroxymethyl)-N-(tert-butoxycarbonyl)pyrrolidine. An
oven-dried, 2-L, three-necked flask, equipped with a magnetic stirring bar and a
thermocouple (Note
4), is charged with
(−)-sparteine (30.2 mL, 131 mmol) (Note
5),
N-Boc-pyrrolidine (15.0 g, 87.6 mmol), and anhydrous
ether (900 mL) (Note
6). The solution is cooled to

−70°C (
dry ice/acetone bath) (Note
4). To this solution is added
sec-butyllithium (96 mL, 1.16 M in
cyclohexane, 111 mmol) (Note
7) and (Note
8) dropwise over a period of 35 min (Note
9). The reaction is then stirred at

−70°C for 5.5 hr (Note
10).
After this interval, a solution of
benzophenone (25.5 g, 140 mmol) (Note
11) in anhydrous
ether (200 mL) is added dropwise over a period of 1.25 hr (Note
9). The dark green to greenish-yellow suspension is maintained at −70°C for 2.0 hr, and the reaction is then quenched by dropwise addition of
glacial acetic acid (8.5 mL, 150 mmol) over a period of 15 min. The resulting lemon-yellow suspension is allowed to warm slowly to room temperature over a period of 12 hr, during which time the mixture becomes cream colored.
After the solution is warmed to 25°C,
5% phosphoric acid (H3PO4) (150 mL) is added to the reaction mixture, and the resulting biphasic mixture is stirred for 20 min. The layers are partitioned and the organic phase is washed with additional
5% H3PO4 (3 × 150 mL). Combined aqueous phases are extracted with
ether (3 × 200 mL). The original organic phase and the ethereal extracts are combined, washed with
brine (200 mL), dried over
magnesium sulfate (MgSO
4), filtered, and the solvents are removed under reduced pressure to afford crude product as an off-white solid. The crude
(R)-(+)-2-(diphenylhydroxymethyl)-N-(tert-butoxycarbonyl)pyrrolidine is purified by recrystallization from a mixture of
hexanes-ethyl acetate (
675 mL, 20 : 1, v/v) affording in two crops
20.9–22.0 g (
73–74%) of analytically pure product as a white solid (Note
12) having greater than 99.5% ee (Note
13).
Sparteine is recovered by making the aqueous phases basic with aqueous
20% sodium hydroxide (NaOH) (160 mL) (Note
14). The aqueous phase is extracted with
Et2O (4 × 150 mL), and the combined organic phases are dried over
potassium carbonate (K
2CO
3), filtered, and the solvents removed under reduced pressure to afford
30.3 g (
98%) of crude, recovered
sparteine as a pale yellow oil (Note
15). Fractional distillation of the residual oil from
calcium hydride (CaH
2) (Note
5) affords
27.0 g of
sparteine (
88%) suitable for reuse.
2. Notes
2. Toward the end of the addition, gas evolution (CO
2) occurs. Care should be taken to provide adequate venting to avoid pressure buildup.
3. The product,
N-Boc-pyrrolidine, has the following spectral characteristics:
1H NMR (CDCl
3, 300 MHz) δ: 1.43 (s, 9 H), 1.81 [s (br), 4 H], 3.27 (m, 4 H);
13C NMR (CDCl
3, 75 MHz) δ 24.78, 25.54, 28.32, 45.38, 45.71, 78.57, 154.41; IR (film) cm
−1: 2974, 2875, 1698, 1403, 1168, 877, 772.
4. The internal temperature was monitored throughout the reaction with an Omega D730 or equivalent thermocouple.
5. Sparteine is liberated from the commercially available sulfate salt (Aldrich Chemical Company, Inc.) as follows:
Sparteine sulfate pentahydrate (100 g, 240 mmol) is dissolved in deionized water (125 mL), and to this solution is slowly added aqueous
20% NaOH (100 mL). The resulting milky-white, oily mixture is then extracted with
ether (4 × 150 mL). The combined ethereal extracts are dried over anhydrous K
2CO
3, filtered, and the solvent is removed under reduced pressure. Vacuum distillation of the residual oil from CaH
2 affords
52 g (
92%) of
sparteine as a clear, colorless to slightly yellow, viscous oil (bp
115–120°C/0.3 mm). The
sparteine free base readily absorbs atmospheric
carbon dioxide (CO
2) and should be stored under
argon at −20°C in a freezer.
6. Anhydrous
ethyl ether was obtained by distillation under
nitrogen from
sodium benzophenone ketyl.
8. The checkers found that the yields obtained in this procedure are critically dependent on the quality of the
sec-butyllithium employed. Best results are obtained with fresh (< 3 months shelf life) commercial samples (FMC Lithium Division, and Aldrich Chemical Company, Inc.) that are colorless to deep yellow, largely free of precipitated salts, and that have been kept refrigerated and have not been exposed to traces of moisture or
oxygen by extensive previous sampling. Samples of
sec-butyllithium that contain alkoxide or hydroxide undergo alkoxide/hydroxide-catalyzed decomposition to
butene and
lithium hydride (LiH), particularly when stored at room temperature; the latter cannot be readily removed. In the hands of the checkers, such aged
sec-butyllithium samples provide the
N-Boc amino alcohol of comparable enantiomeric purity in

5–15% lower yield.
9. During the addition, the internal temperature of the reaction did not exceed −68°C.
10. The reaction mixture became milky white during this interval.
11. Commercially available
benzophenone (Aldrich Chemical Company, Inc., 99+ %) was used without further purification.
12. The product has the following characteristics:
1H NMR (300 MHz, CDCl
3) δ 0.65–0.80 (m, 1 H), 1.40–1.60 (s, 11 H), 1.82–1.95 (m, 1 H), 1.98–2.14 (m, 1 H), 2.75–2.90 (m, 1 H), 3.20–3.45 (m, 1 H), 4.86 (dd, 1 H, J
1 = 8.9, J
2 = 3.8), 7.20–7.45 (m, 10 H, Ar-H);
13C NMR (75 MHz, CDCl
3) δ 22.84, 28.29, 29.67, 47.77, 65.50, 80.54, 81.62, 126.96, 127.00, 127.27, 127.61, 127.77, 128.14, 143.72, 146.41, 159.00; IR (film) cm
−1: 3370, 2979, 1659, 1415, 1164, 763, 70. Anal. Calcd for C
22H
27NO
3: C, 74.76; H, 7.70; N, 3.96. Found: C, 74.62; H, 7.72; N, 4.13.
[α]D25 +150° (CHCl
3,
c 3.62); mp
150.5–152°C. The checkers found
[α]D25 +144° (CHCl
3,
c 3.89).
13. The enantiomeric excess was determined by alkaline ethanolysis of the
Boc group followed by conversion of the amine to the
3,5-dinitrobenzamide. HPLC analysis of a saturated solution of the
benzamide in
5% 2-propanol in
hexane using a Pirkle Covalent S-N1N-Naphthylleucine Column (Regis Chemical Company) with
5% 2-propanol in
hexane as the eluent, and a flow rate of 1.5 mL/min indicates a single peak with retention time of 35 min. HPLC analysis of the corresponding racemic
benzamide affords two peaks at 27 and 32 min corresponding to the (S)- and (R)-enantiomers respectively. The differences in retention times arise from the size of sample that was injected; the
1H NMR of the racemic and enantio-enriched benzamides were identical.
14. The aqueous solution was brought to ca. pH 11 as tested by Hydrion Paper (Micro Essential Laboratories, Brooklyn, NY).
15. The
1H NMR of the recovered
(−)-sparteine was identical to that of pure
(−)-sparteine.
16. The concentration of the reactants is

0.2 M. If more dilute solutions of base are employed (0.01 M), the checkers found that the reaction required at least 24 hr to completion and that impure product was obtained. At higher dilution, formation of significant amounts of the cyclic
urethane was observed, and this by-product required removal by chromatography.
17. The residual, colorless, viscous oil solidified slowly upon exposure to high vacuum.
18. The title compound has the following characteristics:
1H NMR (300 MHz, CDCl
3) δ 1.40–1.95 (m, 5 H), 2.89–3.05 (m, 2 H), 4.23 (t, 1 H, J = 7.4), 4.55 [(s (br), 1 H], 7.10–7.35 (m, 4 H), 7.45–7.60 (m, 6 H);
13C NMR (75 MHz, CDCl
3) δ 25.47, 26.23, 46.71, 64.42, 76.65, 125.47, 125.80, 126.29, 126.40, 127.91, 128.17, 145.36, 148.13; IR (film) cm
−1: 3352, 2968, 1598, 1492, 1448, 1173, 748, 701. Anal. Calcd for C
17H
19NO: C, 80.60; H, 7.56; N, 5.53. Found: C, 80.56; H, 7.60; N, 5.68.
[α]D25 +73.8° (CHCl
3,
c 3.37); mp
76–77°C; R
f = 0.13 (CH
2Cl
2 : MeOH, 95 : 5). The checkers found
[α]D25 +67.9° (CHCl
3,
c 3.37)
All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The approach reported here should facilitate the preparation of α,α-disubstituted-pyrrolidinemethanol analogs. By using this methodology, a single enantio-enriched organolithium intermediate can be treated with a variety of electrophiles (e.g., diaryl ketones) to afford aryl-substituted analogs of the title compound. Previously reported syntheses involve a variety of nucleophilic organometallic reagents that must be prepared and treated with proline derivatives.
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