Resolution of protected silaproline
651
(ESI?): m/z calcd for C18H28NO4Si (M?H)? 350.1788,
found 350.1786. Analytical chiral HPLC (1 mL/min, UV
254 nm, polarimeter) : Chiralpak AD-H (hexane/2-PrOH
9/1): Rt(D,?) = 6.17, Rt(L,-) = 8.72, k(D) = 0.99,
k(L) = 1.82, a = 1.83 and Rs = 5.08, on Chiralpak IC
(hexane/2-PrOH 8/2): Rt(L,-) = 7.66, Rt(D,?) = 11.82,
k(L) = 1.47, k(D) = 2.81, a = 1.91 and Rs = 6.45, on
Chiralpak AS-H (hexane/2-PrOH 9/1): Rt(L,-) = 5.01,
Rt(D,?) = 5.63, k(L) = 0.62, k(D) = 0.82, a = 1.33 and
Rs = 1.54, on Lux-Cellulose-2 (hexane/2-PrOH 9/1):
Rt(L,-) = 7.81, Rt(D,?) = 17.57, k(L) = 1.53, k(D) =
4.67, a = 3.05 and Rs = 9.70 and on Chiralcel OD-H
(hexane/2-PrOH 9/1): Rt(L,-) = 4.75, Rt(D,?) = 6.68,
k(L) = 0.53, k(D) = 1.16, a = 2.17 and Rs = 4.37. For the
(L)-enantiomer, [a]D20 = -35 (c 1, CHCl3).
Synthesis of Fmoc-Sip-OtBu (9) from H-Sip-OtBu (8)
A solution of HCl/dioxane (4 mL, 4 M) in a round-bot-
tom flask equipped with a magnetic stir-bar was cooled
by an ice-water bath under argon. Boc-(D/L)Sip-OtBu
(63 mg, 0.2 mmol) was added in one portion under stir-
ring. The ice-bath was removed and the mixture was kept
stirred. After 30 min, the reaction mixture was condensed
by rotary evaporation in vacuo at room temperature. The
residue H-Sip-OH (8) was then dissolved in dioxane. The
apparent pH of the mixture was maintained at 8–9 during
the reaction by adding triethylamine when necessary. A
solution of Fmoc-Cl (68 mg, 0.26 mmol) in dioxane was
added. The reaction mixture was stirred for 24 h. The
mixture was concentrated in vacuo, and the remaining
residue was dissolved in ethyl acetate. The organic layer
was extracted three times with a saturated solution of
potassium hydrogenocarbonate, and then with water. The
organic phase was dried over anhydrous MgSO4, filtered
and concentrated to afford the Fmoc-(D/L)Sip-OtBu
(80%).
Synthesis of Fmoc-Sip-OH (7) from H-Sip-OH (6)
Boc-(D/L)Sip-OtBu (500 mg, 1.59 mmol) was dissolved in
6 N HCl to pH 2–3 at room temperature, to afford 6 with
quantitative yield.
Oil—Rf = 0.42 (cyclohexane/ethyl acetate 8/2). Two
conf.: 1H-NMR (CDCl3, 300 MHz): d = 0.18 (s, 6 H,
Si(CH3)2), 1.04–1.28 (m, 2 H, SiCH2CH), 1.38 (s, 9 H,
OtBu), 2.74–2.95 (m, 2 H, SiCH2N), 4.10–4.35 (m, 3 H,
CH2CH fluorene), 4.66 (dd, J = 3 Hz, J = 10 Hz, 1 H,
CHa), 7.18–7.70 (m, 8 H, H arom); 13C-NMR (CDCl3,
75 MHz): d = -3.59 and -3.50 (2 s, Si(CH3)2), 14.93 and
16.05 (2 s, SiCH2CH), 26.76 (s, OtBu), 33.05 and 33.66
(2 s, SiCH2N), 46.07 (1 s,CHCH2 fluorene), 58.98 and
59.38 (2 s, CHa), 66.29 and 66.60 (2 s, CHCH2 fluorene),
79.90 and 80.11 (2 s, C(CH3)3), 118.66, 123.92, 125.77,
140.03, 142.87 (8 s, C arom), 155.24 and 155.76 (2 s, C=O
urethane), 171.72 and 171.79 (2 s, C=O ester). HRMS
(ESI?): m/z calcd for C25H32NO4Si (M?H)? 438.2101,
found 438.2097. Analytical chiral HPLC (1 mL/min, UV
254 nm, polarimeter) , Chiralpak AD-H (hexane/2-PrOH
9/1), Rt(D,?) = 11.34, Rt(L,-) = 12.88, k(D) = 2.78,
k(L) = 3.29, a = 1.19 and Rs = 1.32, on Lux-Cellulose-2
(hexane/2-PrOH 9/1): Rt(L,-) = 11.24, Rt(D,?) = 14.93,
k(L) = 2.75, k(D) = 3.98, a = 1.45 and Rs = 3.25 or on
Chiralpak IC (hexane/2-PrOH 7/3): Rt(L,-) = 6.65,
Rt(D,?) = 9.85, k(L) = 1.22, k (D) = 2.28, a = 1.87 and
Rs = 5.63.
After concentration in vacuo H-Sip-OH (6) (107 mg,
0.67 mmol) was dissolved in 9% sodium carbonate solu-
tion (1.5 mL) and cooled in an ice-bath, a solution of
Fmoc-Cl (207.8 mg, 0.80 mmol) in dioxane (3 mL) was
added at 0°C under stirring, which was continued at room
temperature for 24 h. The mixture was diluted with water,
and extracted with ether and ethyl acetate. The remaining
aqueous phase was cooled and acidified with concentrated
hydrochloric acid to pH 2. The aqueous phase was
extracted with ethyl acetate. The organic phase was washed
with saturated sodium chloride solution and water, then
dried over anhydrous MgSO4, filtered and concentrated to
afford the Fmoc-(D/L)Sip-OH (213 mg, 83%).
Oil—Rf = 0.5 (CHCl3/MeOH/AcOH: 120/10/5). Two
conf.: 1H-NMR (CDCl3, 300 MHz): d = 0.20 and 0.30
(2 s, 6 H, Si(CH3)2), 0.9–1.40 (m, 2 H, SiCH2CH),
2.80–3.10 (m, 2 H, SiCH2N), 4.20–4.60 (m, 3 H,
CH2CH fluorene), 473–4.85 (2dd, J = 3 Hz, J = 10 Hz, 1
H, CHa), 7.20–7.80 (m, 8 H, arom H), 10.50 (s, 1 H,
CO2H); 13C-NMR (CDCl3, 75 MHz): d = -2.35 and -
2.05 (2 s, Si(CH3)2), 16.22 and 17.55 (2 s, SiCH2CH),
34.68 and 35.18 (2 s, SiCH2N), 47.67 (s, CHCH2 fluorene),
59.43 and 60.23 (2 s, CHa), 68.28 (s, CHCH2 fluorene),
120.39, 125.40, 125.60, 127;47, 128.05, 141.67, 144.29,
144.51 (8 s, arom C), 156.87 and 157.91 (2 s, C=O ure-
thane), 179.10 and 179.80 (2 s, C=O acid). Analytical
chiral HPLC (1 mL/min, UV 254 nm, polarimeter) :
Chiralpak IC (hexane/ethanol/TFA 9/1/0.1): Rt(L,-) =
10.61, Rt(D,?) = 13.44, k(L) = 2.48, k(D) = 3.41, a =
1.37 and Rs = 3.35. For the (L)-enantiomer, [a]2D0 = -45
(c 1, CHCl3).
Characterisation of 10
1H-NMR (D2O, 300 MHz): d = 0.20 (s, 6H, Si(CH3)2),
1.18 (d, J = 6 Hz, 2H, SiCH2CH), 2.65 (s, 3 H, CH3N),
3.60 (dd, J = 3 Hz, J = 6 Hz 1 H, CHa), MS–ESI?
(CAD): 178 [M?H]?, 160 [M-(H2O)?H]?, 129
[M-(CH3NH2)?H]?.
123