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129.9 (2C), 128.2 (2C), 127.8 (2C), 127.2, 125.20, 125.16, 120.0 (2C),
66.9, 47.4, 38.1, 35.9, À4.4, À4.6 ppm; HRMS: m/z calcd for
C26H27NO4Si: 468.1607 [M+Na]+; found: 468.1588.
10.2 Hz, 1H), 4.19 (t, J=6.7 Hz, 1H), 3.55 (ddt, J=2.9, 10.0, 13.0 Hz,
2H), 3.43 (dt, J=3.0, 11.2 Hz, 1H), 1.84–1.75 (m, 1H), 1.34 (tt, J=
2.7, 13.4 Hz, 1H), 0.38 (s, 3H), 0.30 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=158.6, 143.9, 143.8, 141.5, 153.2, 134.1 (2C), 130.0 (2C),
128.4 (2C), 127.8 (2C), 127.20, 127.17, 125.05, 125.02, 120.13,
120.11, 67.0, 58.3, 47.5, 36.3, 34.0, À4.8, À4.9 ppm; HRMS: m/z
calcd for C26H29NO3Si: 454.1814 [M+Na]+; found: 454.1800.
(R)-N-{(R/S)-4-[(tert-Butyldimethylsilyl)oxy]-2-(methyldiphenylsi-
lyl)butan-2-yl}-2-methylpropane-2-sulfinamide (12’): Lithium
bands (78 mg, 11.3 mmol) were suspended in anhydrous, degassed
THF (4 mL), diphenylmethylchlorosilane (659 mg, 2.83 mmol) was
added and the mixture was stirred for 4 h. In a separate flask, sulfi-
nyl ketimine 7 (172 mg, 0.57 mmol) was dissolved in anhydrous,
degassed THF (4 mL) and cooled to À788C. To this cooled solution,
the silyllithium solution was added dropwise over 5 min and the
reaction was stirred at À788C for 18 h. H2O (5 mL) was added and
the mixture was allowed to warm to RT, poured into H2O, extracted
with EtOAc, dried over MgSO4, and evaporated in vacuo. The crude
mixture contained a 1:1 mixture of the two diastereoisomers. The
two diastereoisomers were separated by FC (EtOAc/pentane, 10%)
to afford the product diastereoisomer 12’ (99 mg, 35%) as a clear
(S/R)-(9H-Fluoren-9-yl)methyl [4-hydroxy-2-(methyldiphenylsilyl)-
butan-2-yl]carbamate (22): The compound was synthesized ac-
cording to general procedure B from sulfinamide 12’ (208 mg,
0.41 mmol). The product was obtained by FC (EtOAc/pentane, 10–
20%) as a colorless foamy solid (98 mg, 47%). 1H NMR (400 MHz,
CDCl3): d=7.76 (d, J=7.6 Hz, 2H), 7.64 (d, J=7.6 Hz, 2H), 7.59 (d,
J=6.9 Hz, 2H), 7.50 (d, J=7.4 Hz, 2H), 7.42–7.26 (m, 10H), 5.32
(br s, 1H), 4.28–4.17 (m, 2H), 4.03 (t, J=6.8 Hz, 1H), 3.83–3.69 (m,
2H), 2.33–2.21 (m, 1H), 1.81–1.70 (m, 1H), 1.46 (s, 3H), 0.77 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=155.9, 144.16, 144.14, 141.39,
141.38, 135.3 (4C), 129.5 (2C), 128.0 (4C), 127.7 (2C), 127.10 (2C),
127.08 (2C), 125.24, 124.21, 120.0 (2C), 66.3, 59.1, 47.4, 45.1, 39.5,
22.7, À4.1 ppm; HRMS: m/z calcd. for C32H33NO3Si: 530.2127
[M+Na]+; found: 530.2124.
1
oil. H NMR (400 MHz, CDCl3): d=7.73 (dd, J=1.6, 7.6 Hz, 2H), 7.63
(dd, J=1.7, 7.4 Hz, 2H), 7.43–7.33 (m, 6H), 3.63 (ddd, J=1.7, 6.6,
8.2 Hz, 2H), 3.36 (s, 1H), 2.16 (ddd, J=6.3, 8.3, 13.9 Hz, 1H), 2.05
(ddd, J=6.6, 8.4, 13.8 Hz, 1H), 1.59 (s, 3H), 1.10 (s, 9H), 0.81 (s,
9H), 0.74 (s, 3H), À0.08 (s, 3H), À0.09 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=135.7 (2C), 135.5 (2C), 134.4, 134.0, 129.9 (2C),
128.2 (2C), 128.1 (2C), 60.4, 56.1, 48.3, 41.9, 26.1 (3C), 25.8, 22.9
(3C), 18.4, À5.2, À5.3, À5.4 ppm; HRMS (-TBS-group): m/z calcd. for
C21H31NO2SSi: 428.1482 [M+K]+; found: 428.1839.
Solid-phase peptide synthesis
General procedure for synthesis of peptides 23, 24, and 25:
Compounds were synthesized according to a modification of the
reported procedure.[25] The peptide was synthesized in a fritted sy-
ringe on a 2-chlorotrityl chloride resin preloaded with phenylalani-
nol (0.15 mmol) by following Method B with a few modifications;[25]
a-aminoisobutyric acid (5, 8 or 13) was substituted for 10, which
was single coupled by using a modified single coupling cycle
(shaking at RT for 60 min instead of MW heating). The two valines
at positions 15 and 9 were coupled as preformed acid fluorides by
using a modified acid fluoride coupling cycle (shaking at RT for
60 min instead of MW heating). Alanine (4) was coupled by using
a modified double coupling cycle (shaking at RT for 60 min instead
of MW heating). The peptide was purified by semipreparative RP-
HPLC (Zorbax column, using a linear gradient from 50–90% B in A
over 25 min with a flow rate of 5 mLminÀ1).
3-({[(9H-Fluoren-9-yl)methoxy]carbonyl}amino)-3-(methyldiphe-
nylsilyl)butanoic acid (13’): The compound was synthesized ac-
cording to general procedure C from carbamate 22 (98 mg,
0.19 mmol). The product was obtained as a pale-yellow foamy
solid (94 mg, 94%). 1H NMR (400 MHz, CDCl3): d=7.75 (d, J=
7.6 Hz, 2H), 7.61 (dd, J=1.6, 4.7 Hz, 2H), 7.60 (dd, J=2.0, 4.5 Hz,
2H), 7.49 (t, J=7.4 Hz, 2H), 7.41–7.32 (m, 8H), 7.29 (tt, J=1.2,
7.4 Hz, 2H), 5.21 (br s, 1H), 4.27 (dd, J=7.2, 10.6 Hz, 1H), 4.21 (dd,
J=6.8, 10.6 Hz, 1H), 4.04 (t, J=6.8 Hz, 1H), 3.16 (d, J=10.0 Hz,
1H), 2.55 (d, J=14.9 Hz, 1H), 1.45 (s, 3H), 0.79 ppm (s, 3H);
13C NMR (100 MHz, CDCl3): d=176.6, 155.9, 144.05, 143.99, 141.35,
141.33, 135.3 (4C), 129.71 (2C), 129.68 (2C), 128.05 (2C), 128.03 (2C),
127.7 (2C), 127.1 (2C), 125.28, 125.25, 120.0 (2C), 66.7, 47.2, 43.6,
41.1, 23.6, À4.0 ppm; HRMS: m/z calcd for C32H31NO4Si: 544.1920
[M+Na]+; found: 544.1633.
Peptide 23: The product was obtained as a lyophilized powder
(50.4 mg, 15% yield, 93% purity). MALDI-TOF MS: m/z calcd. for
C104H160N22O25Si: 2168.1592 [M+Na]+; found: 2168.531.
(S)-(9H-Fluoren-9-yl)methyl [3-hydroxy-1-(methyldiphenylsilyl)-
propyl]carbamate (17): The compound was synthesized according
to general procedure B from sulfinamide 8 (135 mg, 0.28 mmol).
The product was obtained by FC (EtOAc/pentane, 5–33%) as a col-
orless foamy solid (146 mg, 98%). 1H NMR (400 MHz, CDCl3): d=
7.76 (d, J=7.6 Hz, 2H), 7.58–7.49 (m, 5H), 7.46–7.36 (m, 10H),
7.32–7.23 (m, 1H), 4.49–4.44 (m, 2H), 4.39–4.34 (m, 1H), 4.18 (t, J=
6.8 Hz, 1H), 4.02 (ddd, J=2.8, 10.4, 12.8 Hz, 1H), 3.57 (ddd, J=2.4,
5.2, 12.0 Hz, 1H), 3.48 (dt, J=2.8, 11.2 Hz, 1H), 1.93–1.84 (m, 1H),
1.43 (tt, J=2.4, 13.6 Hz, 1H), 0.63 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=158.6, 143.9, 143.7, 141.4 (2C), 134.99 (2C), 134.97 (2C),
133.7, 133.5, 130.1 (2C), 128.41 (2C), 128.38 (2C), 127.81 (2C),
127.78 (2C), 127.2 (2C), 127.1 (2C), 67.1, 58.3, 47.4, 34.9, 34.3,
À5.4 ppm; HRMS: m/z calcd for C31H31NO3Si: 516.1971 [M+Na]+;
found: 516.1974.
Peptide 24: The product was obtained as a lyophilized powder
(54.2 mg, 17% yield, 91% purity). MALDI-TOF MS: m/z calcd. for
C104H160N22O25Si: 2168.1592 [M+Na]+; found: 2168.196.
Peptide 25: The product was obtained as a lyophilized powder
(48.0 mg, 15% yield, 99% purity). MALDI-TOF MS: m/z calcd. for
C104H160N22O25Si: 2168.1592 [M+Na]+; found: 2168.391.
General procedure for synthesis of peptides 26 and 27: The pep-
tides were synthesized in a fritted syringe on a 2-chlorotrityl chlo-
ride resin preloaded with phenylalaninol (0.2 mmol). The resin was
swelled in 1:1 DMF/CH2Cl2 for 30 min and washed three times with
DMF. Acylations were performed by treating the resin with a solu-
tion of Fmoc-amino acid (3 equiv.), PyOxim (3 equiv.), and DIPEA
(6 equiv.) in DMF (1.2 mL) for 30 min [the following amino acids
were double coupled: Aib(16), Val(15), Aib(13), Leu(12), Val(9),
Gln(7), Ala(4), Pro(2) and Aib(1); 11(8) was coupled for 60 min]. A
wash cycle of 3DMF was applied after each operation. Fmoc-de-
protection was performed by treating the resin with a solution of
20% piperine in DMF for 210 min. Acetylation of the N-terminus
was performed by treating the resin with a solution of acetic anhy-
dride (7 equiv.) and DIPEA (14 equiv.) in DMF (1.2 mL) for 2
10 min. Cleavage and deprotection of the peptide was performed
(S)-(9H-Fluoren-9-yl)methyl {1-[dimethyl(phenyl)silyl]-3-hydroxy-
propyl}carbamate (18): The compound was synthesized according
to general procedure B from sulfinamide 9 (179 mg, 0.42 mmol).
The product was obtained by FC (MeOH/CH2Cl2, 1%) as a colorless
1
foamy solid (146 mg, 98%). H NMR (400 MHz, CDCl3): d=7.77 (d,
J=7.6 Hz, 2H), 7.55–7.49 (m, 4H), 7.43–7.38 (m, 5H), 7.31 (ddd, J=
1.1, 3.0, 7.4 Hz, 2H), 4.44 (ddt, J=6.8, 6.8, 10.8 Hz, 2H), 4.38 (d, J=
Chem. Eur. J. 2016, 22, 8358 – 8367
8365
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