The Journal of Organic Chemistry
Note
Et2O (70 mL). The biphasic mixture was washed with 5% aq H3PO4
(2 × 100 mL) and brine (50 mL). The combined organic extracts were
dried over MgSO4, and the solvent was removed under reduced
pressure. The residue (10.8 g, dr 97:3) was submitted to high vacuum
distillation (<0.001 mbar) to give 8 (3.85 g, 35%, 50% brsm, dr 98:2)
as a colorless oil along with recovered starting material 6 (2.47 g,
30%). Bp 110−112 °C (<0.001 mbar). Rf = 0.45 (hexane/EtOAc, 2:1).
(400 MHz, CDCl3, δ/ppm): 4.02−3.89 (m, 1H), 3.89−3.76 (m, 1H),
3.35−3.21 (m, 2H), 2.01−1.89 (m, 1H), 1.89−1.69 (m, 3H), 1.68−
1.55 (m, 1H), 1.50−1.35 (m, 1H), 1.43 (s, 9H), 1.21−1.11 (m, 3H).
13C NMR (100 MHz, CDCl3, rotamers 2:1 (*), δ/ppm): 155.4, 79.4,
66.2, 65.7*, 55.5, 54.5*, 46.2, 45.8*, 45.4, 44.3*, 32.1, 31.1*, 28.4,
23.9, 23.6, 22.8*. IR (neat, ν/cm−1): 3427brs, 2969m, 2931w, 2876w,
1691s, 1669s, 1478w, 1454w, 1392s, 1365s, 1251w, 1166s, 1106s,
1026w, 965w, 921w, 898w, 855w, 772m. HRMS (ESI): m/z calcd for
C12H23NNaO3 [M + Na]+, 252.1570; found, 252.1575. GC (Restek,
Rtx 5Sil MS, 45 °C → 4 °C/min →220 °C, 20 min He): tr/min =
33.7; chiral GC (BGB, BGB 176SE, 50 °C → 2 °C/min →180 °C
He): tr/min = 51.8.
[α]D = +6.4° (c = 1.005, CHCl3) (lit.15 [α]D = +10.9° (c = 0.7,
24
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CHCl3)). H NMR (400 MHz, CDCl3, δ/ppm): 4.89 (br s, 1H),
4.15−3.98 (m, 1H), 3.68−3.53 (m, 1H), 3.26−3.13 (m, 2H), 1.94−
1.69 (m, 3H), 1.55−1.44 (m, 1H), 1.44−1.18 (m, 2H), 1.36 (s, 9H),
1.06 (d, J = 6.2 Hz, 3H). 13C NMR (100 MHz, CDCl3, δ/ppm): 156.3,
79.5, 63.4, 53.6, 46.3, 45.4, 30.9, 28.2, 23.3, 22.4. IR (neat, ν/cm−1):
3443brs, 2969m, 2931w, 2880w, 1692s, 1671s, 1479w, 1455w, 1396s,
1365s, 1304w, 1254w, 1165s, 1132m, 1109s, 1052w, 774w. HRMS
(ESI): m/z calcd for C12H24NO3 [M + H]+, 230.1751; found,
230.1748. GC (Restek, Rtx 5Sil MS, 45 °C → 4 °C/min →220 °C, 20
min He): tr/min = 32.9; chiral GC (BGB, BGB 176SE, 50 °C → 2 °C/
min →180 °C He): tr/min = 49.5.
In order to recover (−)-sparteine (5), the combined aqueous
extracts were basified with 50% NaOH and extracted with Et2O (3 ×
100 mL). The combined organic extracts were dried over MgSO4, and
the solvent was removed under reduced pressure. The recovered
diamine was stored at −20 °C under an argon atmosphere and distilled
before reuse.
(−)-Sparteine (5) was recovered as described above (cf. preparation
of 8).
(+)-Pseudohygroline (4). To a solution of 9 (410 mg, 1.79 mmol,
1.0 equiv) in THF (26 mL) was added LiAlH4 (339 mg, 8.94 mmol,
5.0 equiv) cautiously at 0 °C. The heterogeneous reaction mixture was
refluxed for 14 h; it was then allowed to cool to rt, and aq HCl (1 M,
25 mL) was added at 0 °C. The aqueous layer (pH 1) was washed
with CH2Cl2 (2 × 15 mL), basified with aq NaOH (50%), and
extracted with CH2Cl2 (5 × 25 mL). The combined organic extracts
were dried over MgSO4, and the solvent was removed under reduced
pressure to afford (+)-pseudohygroline (4) (239 mg, 93%, dr 96:4, er
> 99%) as a yellowish oil. [α]D = +103° (c = 1.02, EtOH) (lit.10
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25
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[α]D = +95.4° (c = 0.94, EtOH)). H NMR (400 MHz, CDCl3, δ/
ppm): 5.23 (br s, 1H), 3.91 (mc, 1H), 3.04 (mc, 1H), 2.70 (mc, 1H),
2.39−2.28 (m, 1H), 2.35 (s, 3H), 2.01 (ddd, J = 8.0, 12.5, 16.1 Hz,
1H), 1.81−1.69 (m, 2H), 1.51−1.30 (m, 3H), 1.15 (d, J = 6.2 Hz,
3H). 13C NMR (100 MHz, CDCl3, δ/ppm): 67.4, 65.8, 55.4, 43.0,
42.9, 30.5, 24.2, 22.8. IR (neat, ν/cm−1): 3293brs, 2963s, 2928m,
2874m, 2840m, 2781m, 1446m, 1371m, 1323w, 1218w, 1181w, 1132s,
1074m, 1029s, 957w, 936w, 820w. HRMS (ESI): m/z calcd for
C8H18NO [M + H]+, 144.1383; found, 144.1385. GC (BGB, BGB
176SE, 50 °C → 2 °C/min →140 °C He): tr/min = 31.0.
(+)-Hygroline (2). To a solution of 8 (414 mg, 1.81 mmol, 1.0
equiv) in THF (26 mL) was added cautiously LiAlH4 (343 mg, 9.03
mmol, 5.0 equiv) at 0 °C. The heterogeneous reaction mixture was
refluxed for 14 h; it was then allowed to cool to 0 °C, and aq HCl (1
M, 15 mL) was added. The layers were separated, and the aqueous
layer (pH 1) was washed with CH2Cl2 (2 × 10 mL). The aqueous
solution was basified with aq NaOH (4 M) and extracted with CH2Cl2
(4 × 10 mL). The combined organic extracts were dried over MgSO4,
and the solvent was removed under reduced pressure to afford
(+)-hygroline (2) (223 mg, 86%, dr 98:2) as a yellowish oil which
(S)-tert-Butyl 2-((R)-2-Hydroxypropyl)pyrrolidine-1-carboxy-
late (12). To a solution of (+)-sparteine surrogate 11 (8.05 g, 41.4
mmol, 1.2 equiv) in Et2O (65 mL) was added s-BuLi (30.0 mL, 41.4
mmol, 1.2 equiv, 1.38 M in cyclohexane, plus 10 mL Et2O for
washing) dropwise at −78 °C. The homogeneous solution was stirred
for 10 min, and then a solution of N-Boc pyrrolidine (6) (6.05 mL,
34.5 mmol, 1.0 equiv) in Et2O (7 mL) was added dropwise. After
stirring at −78 °C for 4 h, a precooled solution (−78 °C) of (R)-
propylene oxide (7a) (4.20 mL, 60.0 mmol, 1.74 equiv) in Et2O (7
mL) was added dropwise followed by the dropwise addition of a
solution of BF3·OEt2 (7.40 mL, 60.1 mmol, 1.74 equiv) in Et2O (5
mL) over a period of 20 min. After stirring at −78 °C for 2 h, the
reaction mixture was allowed to warm to 0 °C over 45 min. The
reaction was quenched by the addition of water (66 mL), and the
mixture was diluted with Et2O (70 mL). The biphasic mixture was
washed with 5% aq H3PO4 (2 × 100 mL) and brine (50 mL). The
combined organic layers were dried over MgSO4, and the solvent was
removed under reduced pressure. The residue (7.82 g, dr 97.5:2.5) was
submitted to high vacuum distillation (<0.001 mbar) to give 12 (4.48
g, 57%, 65% brsm, dr 96.5:3.5) as a colorless oil along with recovered
starting material 6 (702 mg, 12%). Bp 114−116 °C (<0.001 mbar). Rf
= 0.21 (hexane/EtOAc, 2:1). [α]D24 = −56.9° (c = 1.04, CHCl3) (lit.17
24
solidified upon storage in the freezer. Mp 30−32 °C. [α]D = +47.4°
(c = 1.035, EtOH) (lit.10 [α]D25 = +49.6° (c = 1.28, EtOH)). 1H NMR
(400 MHz, CDCl3, δ/ppm): 6.54 (br s, 1H), 4.14 (mc, 1H), 3.06 (mc,
1H), 2.56 (mc, 1H), 2.33 (s, 3H), 2.18−2.08 (m, 1H), 1.95−1.64 (m,
5H), 1.41 (td, J = 2.4, 14.6 Hz, 1H), 1.13 (d, J = 6.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3, δ/ppm): 64.8, 64.5, 57.0, 40.5, 37.0, 28.2,
23.6, 23.3. IR (neat, ν/cm−1): 3304brs, 2964s, 2927m, 2876m, 2843m,
2790s, 1456s, 1374m, 1291w, 1208m, 1186m, 1135s, 1117m, 1069s,
1037m, 951m, 931m, 901m. HRMS (ESI): m/z calcd for C8H18NO
[M + H]+, 144.1383; found, 144.1384. Chiral GC (BGB, BGB 176SE,
50 °C → 2 °C/min →140 °C He): tr/min = 26.5.
(R)-tert-Butyl 2-((S)-2-Hydroxypropyl)pyrrolidine-1-carboxy-
late (9). To a solution of (−)-sparteine (5) (4.92 g, 20.1 mmol, 1.2
equiv) in Et2O (33 mL) was added dropwise at −78 °C s-BuLi (15.6
mL, 20.9 mmol, 1.2 equiv, 1.34 M in cyclohexane). The homogeneous
solution was stirred for 10 min, and then a solution of N-Boc-
pyrrolidine (6) (3.10 mL, 17.7 mmol, 1.0 equiv) in Et2O (8 mL) was
added dropwise. After stirring at −78 °C for 4 h, a precooled solution
(−78 °C) of (S)-propylene oxide (7b) (2.50 mL, 35.7 mmol, 2.0
equiv) in Et2O (4.5 mL) was added dropwise followed by the
dropwise addition of a solution of BF3·OEt2 (4.40 mL, 35.7 mmol, 2.0
equiv) in Et2O (4.5 mL) over a period of 15 min. After stirring for 2 h
at −78 °C, the reaction mixture was allowed to warm to 0 °C over 30
min, the reaction was quenched at 0 °C with water (40 mL), and then
the mixture was diluted with Et2O (40 mL). The biphasic mixture was
washed with 5% aq H3PO4 (2 × 60 mL) and brine (30 mL). The
combined aqueous layers were back-extracted with Et2O (70 mL), and
the organic extract was washed with 5% aq H3PO4 (15 mL) and brine
(10 mL). The combined organic extracts were dried over MgSO4, and
the solvent was removed under reduced pressure. The residue (6.07 g,
dr 94.5:5.5) was submitted to high vacuum distillation (<0.001 mbar)
to give 9 (2.45 g, 60%, 64% brsm, dr 94.5:5.5) as a colorless oil along
with recovered starting material 6 (173 mg, 6%). Bp 114−116 °C
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[α]D = −80.2° (c = 0.1, CHCl3)). H NMR (400 MHz, CDCl3, δ/
ppm): 3.99−3.87 (m, 1H), 3.87−3.73 (m, 1H), 3.39−3.18 (m, 2H),
1.92 (mc, 1H), 1.86−1.68 (m, 3H), 1.68−1.51 (m, 1H), 1.45−1.31 (m,
1H), 1.40 (s, 9H), 1.21−1.07 (m, 3H). 13C NMR (100 MHz, CDCl3,
rotamers 2:1 (*), δ/ppm): 155.4, 79.4, 66.2, 65.6*, 55.4, 54.5*, 46.2,
1
45.8*, 45.3, 44.2*, 32.0, 31.1*, 28.4, 23.9, 23.6, 22.8*. H NMR (400
MHz, DMSO-d6, δ/ppm) (1:1 mixture of rotamers): 4.32 (s, 1H),
3.93−3.74 (m, 1H), 3.71−3.51 (m, 1H), 3.30−3.08 (m, 2H), 1.95−
1.57 (m, 5H), 1.39 (s, 9H), 1.32−1.14 (m, 1H), 1.06 (d, J = 6.1 Hz,
3H). 13C NMR (100 MHz, DMSO-d6, δ/ppm) (1:1 mixture of
rotamers (*)): 153.3, 77.8, 63.5, 54.0, 45.9, 45.6*, 43.5, 42.9*, 30.3,
29.4*, 28.1, 24.1, 23.1, 22.4*. IR (neat, ν/cm−1): 3418brs, 2969m,
2935w, 2881w, 1691s, 1670s, 1478w, 1455w, 1401s, 1366m, 1252w,
1169s, 1110m, 1061w, 774w. HRMS (ESI): m/z calcd for
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(<0.001 mbar). Rf = 0.21 (hexane/EtOAc, 2:1). [α]D = +58.4° (c =
1.015, CHCl3) (lit.15 [α]D = +78.5° (c = 1.00, CHCl3)). H NMR
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C
dx.doi.org/10.1021/jo4017343 | J. Org. Chem. XXXX, XXX, XXX−XXX