The Journal of Organic Chemistry
Note
+
signals: s = singlet; d = doublet; t = triplet; m = multiplet; br = broad
and combinations thereof. The chemical shifts are calibrated to TMS
HRMS (ESI): calcd for C H NO S (MH) 484.1946, found
30 30 3
484.1952.
(
δ H 0.00) or residual proton and carbon resonances of the solvent
Removal of the Chiral Auxiliary to Furnish (R )-2. Thiolester
(R ,S)-4f (53 mg, 0.108 mmol) was dissolved in dry THF (1 mL). The
P
P
CDCl (δ H 7.26 and δ C 77.16). IR spectra were recorded on an
3
ATR-FT-IR instrument equipped with a diamond ATR probe. Mass
spectra were obtained with a QTOF LC/MS instrument. Enantio-
meric excesses were determined by chiral HPLC equipped with a
photodiode array detector (200−400 nm) and an IA column (5 μm;
size 250 mm × 4.6 mm). In all cases, the analysis was calibrated with a
resulting mixture was cooled to −78 °C, and LiAlH (49.6 mg, 1.34
4
mmol) was added portionwise. The solution was stirred for 15 min,
and the cold bath was removed. After stirring at room temperature for
24 h, the resulting mixture was poured into an aqueous 1 M HCl (30
mL)/ice mixture. The precipitate was extracted with CH Cl (3 × 40
2
2
−1
sample of the racemate. Optical rotations are reported in deg dm
mL), and the organic fractions were combined, dried over MgSO4,
filtered, and evaporated to dryness. The resulting crude product was
then purified by passing through a small plug of silica gel (n-pentane/
CH Cl , 90:10) to afford thiol (R )-2 as a colorless solid. Yield 96%
3
−1
cm g and were measured at room temperature (20 °C) on a
polarimeter using a 1 mL cell with a 1 dm path length at 589 nm
(
sodium D light). (±)-[2.2]Paracyclophane-4-thiol (±)-2 was
2
2
P
17c
17c
prepared as previously reported by us.
(25.1 mg, 0.104 mmol, >99% ee). Mp: 139−141 °C (lit. mp 140
20
D
Resolution Protocol with L-Leucine Derivative 3f. (2S)-2-(1,3-
°C). [α] −219.8 (c 0.01, CHCl ). TLC (n-pentane/CH Cl , 90:10)
1
3
2
2
2
9
Dioxoisoindolin-2-yl)-4-methylpentanoic Acid (5). Phthalic anhy-
dride (1.49 g, 8.00 mmol, 1 equiv), L-leucine (1.05 g, 8.00 mmol, 1
equiv), and triethylamine (0.11 mL, 0.8 mmol, 10 mol %) were
dissolved in toluene (20 mL), and the resulting mixture was heated at
reflux for 2 h. After cooling to room temperature, the volatiles were
removed under vacuum. The resulting crude product was washed with
an aqueous 1 M HCl solution (20 mL) and extracted with CH Cl (3
R = 0.22. H NMR (CDCl , 400 MHz) δ 2.81 (ddd, J = 13.5, 10.6,
f
3
and 6.0 Hz, 1H), 2.86−2.95 (m, 1H), 2.98−3.12 (m, 4H), 3.14 (s,
1H), 3.26 (ddd, J = 13.0, 10.0, and 6.0 Hz, 1H), 3.37−3.47 (m, 1H),
6.21 (d, J = 1.5 Hz, 1H), 6.37−6.49 (m, 3H), 6.50 and 6.60 (AB part
of ABMX system, J = 7.8, J = 1.6 and J = 1.8 Hz, 2H), 7.21 (dd,
AB
AM
BX
13
J = 7.8 and 2.0 Hz, 1H). C NMR (CDCl , 101 MHz) δ 33.2, 34.8,
3
2
2
35.0, 35.5, 127.8, 130.6, 131.7, 132.1, 132.9, 133.5, 134.9, 135.7, 138.6,
−1
×
30 mL) to give the desired carboxylic acid 5 as a white solid (1.79 g,
.86 mmol, 86%). The material was pure enough to be used in the
139.3, 139.4, 140.5. IR (neat, ATR probe, cm ) ν: 713, 793, 804, 849,
+
6
897, 1059, 2925. MS (EI): m/z (%) 240 (M , 100), 207 (37), 136
next step of the synthesis without further purification. Mp: 120−122
(58), 121 (15), 104 (55), 91 (38), 78 (25). HPLC: t = 5.16 min; IA
R
C. [α]2 −16.4 (c 0.1, CHCl ), H NMR (CDCl , 400 MHz) δ 0.92
0
1
−1
°
(
(
column (5 μm; size 250 mm × 4.6 mm); flow rate = 1.0 mL min ; n-
D
3
3
d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H), 1.40−1.58 (m, 1H), 1.95
ddd, J = 14.3, 10.1, and 4.4 Hz, 1H), 2.36 (ddd, J = 14.3, 11.5, and 4.1
heptane/EtOH/MeOH 95:2.5:2.5; 20 °C, 210 nm.
Resolution Protocol with L-Isoleucine Derivative 3g. (2S,3S)-
3
1
Hz, 1H), 5.00 (dd, J = 11.5 and 4.4 Hz, 1H), 7.71−7.74 (m, 2H),
2-(1,3-Dioxoisoindolin-2-yl)-3-methylpentanoic Acid (6). Phthalic
anhydride (741 mg, 5 mmol, 1 equiv), L-isoleucine (659 mg, 5 mmol, 1
equiv), and triethylamine (69 μL, 0.5 mmol) were dissolved in toluene
(8 mL), and the resulting mixture was heated at reflux for 2 h. After
cooling to room temperature, the volatiles were removed under
vacuum. The resulting crude product was washed with an aqueous 1 M
HCl solution (20 mL) and extracted with CH Cl (3 × 30 mL) to give
1
3
7
1
1
1
.84−7.87 (m, 2H), 9.5−11 (very broad s, 1H). C NMR (CDCl ,
3
01 MHz) δ 21.0, 23.1, 25.1, 37.0, 50.4, 123.6, 131.7, 134.2, 167.7,
75.7. IR (neat, ATR probe, cm ) ν: 2935, 1707 (CO), 1465,
−1
384, 1288, 1276, 928, 717.
(
2S)-2-(1,3-Dioxoisoindolin-2-yl)-4-methylpentanoyl Chloride
30
(
3f). Carboxylic acid 5 (196 mg, 0.75 mmol, 1 equiv) and thionyl
2
2
chloride (0.27 mL, 3.75 mmol, 5 equiv) were dissolved in toluene (10
mL). Three drops of DMF were added, and the resulting mixture was
heated at reflux for 3 h. After cooling to room temperature, the
volatiles were removed under vacuum to furnish the desired acid
chloride 3f as a dark yellow oil (209 mg, 0.75 mmol, quantitative). The
the desired carboxylic acid 6 as a white solid (1.28 g, 4.91 mmol, 98%):
3
1
20
Mp 107−109 °C (lit. mp 123−125 °C). [α]D −28 (c 0.1, CHCl ).
3
1
H NMR (CDCl , 400 MHz) δ 0.81 (t, J = 7.4 Hz, 3H), 1.02−1.13
3
(m, 1H), 1.06 (d, J = 6.7 Hz, 3H), 1.44−1.50 (m, 1H), 2.41−2.48 (m,
1H), 4.59 (d, J = 8.2 Hz, 1H), 7.70−7.77 (m, 2H), 7.84−7.89 (m,
13
product was used immediately in the next step without further
2H), 8.80−10.15 (br s, 1H). C NMR (CDCl , 101 MHz) δ 10.9,
3
1
purification. H NMR (CDCl , 250 MHz) δ 0.94 (d, J = 6.7 Hz, 3H),
16.7, 25.8, 34.4, 57.1, 123.7, 131.6, 134.3, 167.8, 173.6. IR (neat, ATR
3
−1
0
.96 (d, J = 6.7 Hz, 3H), 1.38−1.60 (m, 1H), 2.04 (ddd, J = 14.3, 10.0,
probe, cm ) ν: 3223 (OH), 2966, 2930, 1770 (CO), 1710 (C
and 4.3 Hz, 1H), 2.27−2.43 (m, 1H), 5.12 (dd, J = 11.1 and 4.3 Hz,
O), 1610, 1466, 1385, 1190, 1082, 905, 719. HRMS (ESI, negative
13
−
1H,), 7.72−7.74 (m, 2H), 7.84−7.87 (m, 2H). C NMR (CDCl , 101
ionization mode) calcd for C H NO [M − H] : 260.0923; found:
3
14 14
4
MHz) δ 21.0, 23.0, 25.1, 37.3, 59.1, 123.9, 131.5, 134.7, 167.0, 172.1.
Conversion into Thiolester 4f and Diastereoisomer Separation.
Racemic [2.2]paracyclophane-4-thiol (±)-2 (192 mg, 0.8 mmol, 1
equiv) was dissolved in dry CH Cl (10 mL) at room temperature. A
260.0919.
(2S,3S)-2-(1,3-Dioxoisoindolin-2-yl)-3-methylpentanoyl Chloride
29
(3g). In a round-bottomed flask, fitted with a condenser and a
nitrogen inlet, carboxylic acid 6 (199 mg, 0.76 mmol, 1 equiv) and
thionyl chloride (0.28 mL, 3.8 mmol, 5 equiv) were dissolved in dry
toluene (10 mL). Three drops of DMF were added, and the resulting
mixture was heated at reflux for 3 h. After cooling to room
temperature, the volatiles were removed under vacuum to furnish
the desired acid chloride 3g as a dark yellow oil (211 mg, 0.75 mmol,
2
2
solution of freshly prepared acid chloride 3f (1 mmol, 1.25 equiv) in
CH Cl (5 mL) and triethylamine (125 μL, 0.88 mmol, 1.1 equiv)
2
2
were successively added dropwise. The reaction mixture was stirred at
room temperature for 20 h, washed successively with a saturated
aqueous NaHCO3 solution and water, dried over MgSO , and
4
concentrated in vacuo. Purification of the resulting crude product by
quantitative yield). The product was used directly in the next step
1
column chromatography (n-pentane/Et O, 80:20) allowed isolation of
without further purification. H NMR (CDCl , 400 MHz) δ 0.87 (t, J
2
3
a pure fraction of the less polar diastereoisomer (R ,S)-4f
= 7.4 Hz, 3H), 1.07−1.10 (m, 1H), 1.13 (d, J = 6.7 Hz, 3H), 1.39−
P
(
(
configuration assigned by an X-ray analysis). Mp: 69−70 °C.
P
1.50 (m, 1H), 2.50−2.57 (m, 1H), 4.81 (d, J = 8.6 Hz, 1H), 7.79−7.93
(m, 4H). 13C NMR (CDCl , 101 MHz) δ 10.8, 16.5, 25.5, 35.1, 65.9,
R ,S)-S-[2.2]Paracyclophan-4-yl 2-(1,3-dioxoisoindolin-2-yl)-4-
3
−1
methylpentanethioate [(R ,S)-4f]. TLC (n-pentane/Et O, 70:30) R
124.0, 131.5, 134.7, 167.1, 169.9. IR (neat, ATR probe, cm ) ν: 2970,
P
2
f
0
1
=
0.48. [α]2 −57.8 (c 0.1, CHCl ). H NMR (CDCl , 250 MHz) δ
1804 (CO), 1716 (CO), 1468, 1378, 1081, 873, 725.
D
3
3
0
.95 (d, 6H, J = 6.5 Hz), 1.41−1.62 (m, 1H), 2.04 (ddd, J = 14.2, 10.0,
and 4.3 Hz, 1H), 2.41 (ddd, J = 14.2, 11.3, and 4.1 Hz, 1H), 2.77−3.14
m, 7H), 3.32 (ddd, J = 12.6, 9.7, and 2.8 Hz, 1H), 5.08 (dd, J = 11.3
and 4.3 Hz, 1H), 6.29−6.33 (m, 1H), 6.44−6.52 (m, 4H), 6.57−6.59
Conversion into Thiolester 4g and Diastereoisomer Separation.
Racemic [2.2]paracyclophane-4-thiol (±)-2 (500 mg, 2.1 mmol, 1
equiv) was dissolved in dry CH Cl (26 mL). A solution of freshly
(
2
2
prepared acid chloride 3g (733 mg, 2.6 mmol, 1.2 equiv) in dry
1
3
(
m, 2H), 7.8−7.84 (m, 2H), 7.90−8.01 (m, 2H). C NMR (CDCl ,
CH Cl (13 mL) and triethylamine (320 μL, 2.3 mmol, 1.1 equiv)
3
2
2
1
1
1
+
01 MHz) δ 21.1, 23.2, 25.2, 34.2, 34.7, 34.9, 35.3, 37.0, 58.1, 123.8,
27.5, 130.1, 131.8, 132.2, 133.1, 133.3, 134.5, 134.7, 135.1, 138.9,
39.4, 139.5, 140.3, 143.9, 167.8, 194.6. MS (ESI) m/z (%) 989 [(2M
were added successively dropwise. The reaction mixture was stirred at
room temperature for 48 h, washed successively with a saturated
aqueous NaHCO3 solution and water, dried over MgSO , and
4
+
+
+
Na) , 15), 506 [(M + Na) , 53], 484 [(M + H) , 67], 216 (100).
concentrated in vacuo. Fractional crystallization of the resulting crude
3
964
J. Org. Chem. 2016, 81, 3961−3966