Journal of Medicinal Chemistry
Article
1
+
=
0.31 (hexanes/EtOAc, 2:1); mp = 80 °C; H NMR (400 MHz,
MHz, D O) δ 181.4, 69.2, 22.1; HRMS (ESI) m/z [M + Na] calcd
2
CDCl ) δ = 7.76 (d, J = 7.5, 2H), 7.59 (d, J = 6.1, 2H), 7.40 (t, J = 7.4,
for C H O Na 113.0209; found 113.0204.
3
3
6
3
2
4
1
0
1
4
H), 7.31 (t, J = 7.2, 2H), 5.43 (d, J = 7.1, 1H), 4.45−4.34 (m, 3H),
.21 (t, J = 6.8, 1H), 3.68 (s, 3H), 3.13−2.91 (m, 2H), 2.65−2.42 (m,
H), 1.91−1.83 (m, 1H), 1.75−1.47 (m, 1H), 1.45−1.09 (m, 5H),
Benzyl (R)-2-Hydroxypropanoate (11). (R)-Lactic acid (10; 50.0
mg, 0.560 mmol) was dissolved in methanol (3.0 mL), and a 20%
aqueous solution of Cs CO was added until pH 7. The mixture was
concentrated by rotatory evaporation, yielding a white precipitate,
which was dissolved in DMF (2.0 mL), and benzyl bromide (66 μL,
0.560 mmol) was added under stirring. The resulting mixture was
stirred for 6 h at room temperature before it was partitioned between
EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted
twice more with EtOAc (20 mL), the combined organic layers were
2
3
.96 (t, J = 7.3, 3H); 13C NMR (101 MHz, CDCl ) δ 207.4, 176.1,
3
56.2, 144.0, 141.4, 127.8, 127.2, 125.2, 120.1, 67.0, 59.6, 52.0, 47.3,
+
3.4, 34.4, 33.7, 18.5, 17.3, 14.0; HRMS (ESI) m/z [M + Na] calcd
for C H O NNa 446.1938; found 446.1928.
25
29
5
tert-Butyl (R)-2-(((Trifluoromethyl)sulfonyl)oxy)propanoate (2b).
tert-Butyl-(R)-lactate (3.00 g, 20 mmol) was dissolved in dry CH Cl2
2
(
80 mL), and the reaction mixture was cooled to 0 °C under an argon
dried over anhydrous MgSO , and the solvent was removed in vacuo to
4
atmosphere. 2,6-Lutidine (3.49 mL, 30 mmol) was added giving rise to
bubble formation, and then triflic anhydride (4.71 mL, 28 mmol) was
added over a period of 70 min using a syringe pump, upon which the
solution turned purple and then dark yellowish. The reaction mixture
was stirred for an additional 1 h at 0 °C and then diluted with
petroleum ether 40-60 (100 mL) forming a rusty colored oil. An
additional 300 mL of petroleum ether 40-60 was added, and the
organic layer was washed with a mixture of 1 M HCl and a saturated
give the title compound as a colorless liquid/oil containing traces of
1
water (75 mg, 75%). H NMR (400 MHz, CDCl ) δ 7.42−7.33 (m,
3
5H), 5.22 (s, 2H), 4.37−4.28 (m, 1H), 2.76 (d, J = 5.3, 1H), 1.44 (d, J
= 6.9, 3H); 13C NMR (101 MHz, CDCl ) δ 175.7, 135.3, 128.8, 128.7,
3
+
128.4, 67.5, 67.0, 20.5; HRMS (ESI) m/z [M + Na] calcd for
C H O Na 203.0679; found 203.0679.
10
12
3
Benzyl (R)-2-(((Trifluoromethyl)sulfonyl)oxy)propanoate (2c). To
a cold solution (0 °C) of the benzyl lactate 11 (0.957 g, 5.32 mmol) in
aqueous solution of NaCl (1:3, 3 × 200 mL), dried over MgSO , and
CH Cl (21.0 mL) was added triflic anhydride (0.940 mL, 5.59 mmol)
4
2
2
concentrated by rotatory evaporation. The crude whiteish liquid was
purified by isocratic flash column chromatography using a mixture of
CH Cl and petroleum ether (1:1) as the eluent, giving the title
followed by slow addition of 2,6-lutidine (0.620 mL, 5.32 mmol)
under stirring. After 1 h of stirring, the reaction solution was
concentrated by rotatory evaporation, dissolved in hexanes (100 mL),
and cooled in a dry ice bath for several minutes, thus leading to the
precipitation of the lutidinium salt. The precipitate was filtered off and
washed with hexanes, and the combined filtrate was concentrated to
give the title compound as a colorless liquid (1.05 g, 63%). The triflate
2
2
compound as a colorless liquid (4.97 g, 89%). R = 0.79 (CH Cl /
f
2
2
1
petroleum ether; 1:1); H NMR (400 MHz, CDCl ) δ 5.09 (q, J = 7.0,
3
1
H), 1.66 (d, J = 7.0, 3H), 1.51 (s, 9H); 13C NMR (101 MHz, CDCl )
3
D
δ 166.6, 118.5 (q, JC,F = 319.4 Hz), 84.5, 80.7, 27.9, 18.1; [α] +37.5
c = 1.29, CHCl ); HRMS (ESI) m/z [M + H] calcd for C H F O S
25
+
1
(
was used in the next step without further purification. H NMR (400
3
8
14
3
5
2
79.0514; found 279.0513.
MHz, CDCl ) δ 7.44−7.27 (m, 5H), 5.32−5.17 (m, 3H), 1.71 (d, J =
3
(
2R,5S)-5-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-2-meth-
7.0, 3H); 13C NMR (101 MHz, CDCl ) δ 167.4, 134.5, 129.0, 128.9,
3
yl-4-oxooctanoic Acid (4). The tert-butyl keto ester 1 (2.54 g, 5.80
mmol) was dissolved in dry THF (22.3 mL) and added dropwise at
128.6, 118.6 (q, J = 319.8 Hz), 80.1, 68.4, 18.2; HRMS (DART) m/
C,F
+
z [M + H O] calcd for C H F O S 330.0385; found 330.0382.
2
11 13
3
6
−
5 °C to a stirred suspension of NaH (60% in mineral oil, 0.280 g,
.96 mmol) in dry THF (22.3 mL). The resulting pale yellowish
mixture was stirred for 20 min at −5 °C followed by addition of triflate
b (1.77 g, 6.38 mmol) dissolved in dry THF (11.2 mL). After 3 h of
Allyl (S)-4-((tert-Butoxycarbonyl)amino)-3-oxoheptanoate (13).
CDI (1.13 g, 6.95 mmol) was added to a stirring solution of Boc-Nva-
OH (12) (1.44 g, 6.62 mmol) in dry THF (13.5 mL) at room
temperature under argon atmosphere. The yellowish solution was
stirred for 1 h and used in the next step without further purification.
During this hour, a lithium enolate solution was prepared by adding n-
BuLi (9.28 mL, 2.5 M) to a solution of diisopropylamine (3.28 mL,
23.2 mmol) in dry THF (22.1 mL) at 0 °C. The resulting orange
solution was stirred additionally for 10 min and then cooled to −78 °C
followed by dropwise addition of allyl acetate (2.50 mL, 23.2 mmol) in
dry THF (7.4 mL) and stirring for 15 min. The activated amino acid
solution was added dropwise to the lithium enolate solution at −78 °C
under inert conditions, and the resulting mixture was stirred for 40
min and then quenched at the same temperature by addition of a 10%
aqueous citric acid solution (70 mL). After reaching ambient
temperature, the aqueous layer was extracted with EtOAc (3 × 50
mL), and the combined organic layers were washed with saturated
sodium bicarbonate solution (2 × 100 mL) and a saturated aqueous
6
2
stirring at room temperature, the reaction mixture was quenched by
addition of 1 M HCl (170 mL), extracted with EtOAc (3 × 110 mL),
washed with a saturated aqueous solution of NaCl (335 mL), and
finally dried over MgSO . The resulting solution was concentrated by
rotatory evaporation to give a honey-like oil, which was dissolved in
4
CH Cl (58 mL) and trifluoroacetic acid (8.7 mL). After 24 h of
2
2
stirring, the dark green solution was concentrated by rotatory
evaporation, and the obtained brownish oil was dissolved in
dichloromethane (110 mL) and washed with a saturated aqueous
solution of NaCl (1 × 110 mL). The organic layer was dried over
MgSO and concentrated by rotatory evaporation to a dark brownish
oil, which was purified by flash column chromatography using CH Cl2
4
2
and MeOH (97.5:2.5 to 95:5) to give the title compound as a white
foam (0.800 g, 34% over three steps). Mp = decomp; R = 0.28
f
1
(
CH Cl /MeOH, 95:5); H NMR (400 MHz, CDCl ) δ 7.76 (d, J =
solution of NaCl (100 mL) and dried over anhydrous MgSO . The
2
2
3
4
7
2
3
1
.5, 2H), 7.59 (d, J = 6.9, 2H), 7.40 (t, J = 7.4, 2H), 7.31 (t, J = 7.4,
H), 5.45 (d, J = 7.4, 1H), 4.49−4.27 (m, 3H), 4.21 (t, J = 6.8, 1H),
.10−2.92 (m, 2H), 2.54 (dd, J = 20.7, 7.1, 1H), 1.95−1.79 (m, 1H),
solvent was removed to give an orange-colored oily liquid as the crude
product, which in turn was purified using a Reveleris automatic flash
system using a mixture of hexane and EtOAc as eluents (9:1 to pure
EtOAc). The title compound was obtained as a colorless oil (1.66 g,
13
.62−1.47 (m, 1H), 1.42−1.11 (m, 5H), 0.94 (t, J = 7.1, 3H);
C
1
NMR (101 MHz, CDCl ) δ 207.3, 181.1, 156.2, 144.0, 143.9, 141.5,
84%). R = 0.63 (hexane/EtOAc, 9:1); H NMR (400 MHz, CDCl ) δ
3
f
3
1
27.9, 127.2, 125.2, 120.1, 67.1, 59.5, 47.3, 43.1, 34.4, 33.6, 18.4, 17.1,
5.99−5.83 (m, 1H), 5.38−5.20 (m, 2H), 5.05 (d, J = 7.3, 1H), 4.63
(dd, J = 4.6, 1.2, 2H), 4.39−4.26 (m, 1H), 3.65−3.45 (m, 2H), 1.91−
1.70 (m, 1H), 1.64−1.48 (m, 1H), 1.43 (s, 9H), 1.36 (m, 2H), 0.93 (t,
D
+
1
3.9; [α] 25 +27.4 (c = 1.01, CHCl ); HRMS (ESI) m/z [M + H]
3
calcd for C H NO 410.1968; found 410.1969.
24
28
5
J = 7.3, 3H); 13C NMR (101 MHz, CDCl ) δ 202.4, 166.7, 155.6,
(R)-2-Hydroxypropanoic Acid (10). To a stirred solution of D-
3
alanine (9; 0.222 g, 2.50 mmol) in 0.7 M aqueous TFA (4.9 mL) at
room temperature was added a solution of sodium nitrite (0.259 g,
131.6, 119.0, 80.2, 66.2, 59.7, 46.3, 33.1, 28.4, 18.7, 13.9; HRMS (ESI)
+
m/z [M + Na] calcd for C H O NNa 322.1625; found 322.1630.
15
25
5
3
.75 mmol) in milliQ water (2.5 mL) over a period of 3 h using a
Benzyl (2R,5S)-5-((tert-Butoxycarbonyl)amino)-2-methyl-4-ox-
ooctanoate (14). The keto allyl ester 13 (0.871 g, 2.91 mmol) was
dissolved in dry THF (11.0 mL) and added dropwise at −20 °C to a
stirring suspension of NaH (60% in mineral oil, 0.140 g, 3.49 mmol) in
dry THF (11.0 mL). The resulting mixture was stirred for 40 min at
−20 °C followed by addition of the triflate 2c (0.999 g, 3.20 mmol)
dissolved in dry THF (6.0 mL). The resulting yellow solution was
syringe pump. The reaction mixture was left under stirring for
additional 3 h, and NaCl (0.500 g) was added. The aqueous solution
was extraction with EtOAc (4 × 15 mL), the combined organic layers
were dried over MgSO , and the solvent was removed to give the title
4
1
compound as a yellowish oil (0.139 g, 62%). H NMR (400 MHz,
D O) δ 4.34 (q, J = 7.0, 1H), 1.37 (d, J = 7.0, 3H); C NMR (101
13
2
I
dx.doi.org/10.1021/jm500782s | J. Med. Chem. XXXX, XXX, XXX−XXX