Journal of Medicinal Chemistry
Article
(75 mL). After separation, the aqueous phase was extracted with EtOAc
(2 × 75 mL) and the combined organic phases were washed with brine
(100 mL), dried over MgSO4, filtered, concentrated in vacuo, and
purified using DCVC (dia = 4 cm, 30 mL fractions, 0−2% EtOAc in
containing EtOAc (25 mL). The aqueous phase was extracted with
EtOAc (2 × 50 mL), and the combined organic phases were washed
with brine (50 mL), dried over MgSO4, filtered, concentrated in vacuo,
and purified using DCVC (dia = 3 cm, 25 mL fractions, 0−90% EtOAc
in heptane) to yield diol 9b (736 mg, 92%) as a clear, colorless oil. 1H
NMR (300 MHz, CDCl3): δ 6.84−6.78 (2H, m), 6.70 (1H, m), 5.07
(1H, m), 4.65 (2H, s), 3.92 (2H, t, J = 7 Hz), 3.90−3.68 (3H, m), 3.62
(1H, dd, J = 11, 7 Hz), 3.35 (1H, m), 2.86 (1H, m), 2.15 (1H, m), 2.07−
1.90 (2H, m), 1.81 (2H, h, J = 7 Hz), 1.51 (9H, s), 1.05 (3H, t, J = 7 Hz).
13C NMR (75 MHz, CDCl3): δ 159.7, 156.8, 142.9, 142.5, 118.2, 113.6,
1
toluene) to yield 8c (976 mg, 60%) as a clear, colorless oil. H NMR
(300 MHz, CDCl3): δ 7.47−7.30 (5H, m), 6.86 (1H, m), 6.80−6.71
(2H, m), 5.06 (2H, s), 4.71 (2H, s), 4.05 (0.5H, dd, J = 10, 4 Hz), 3.86
(0.5H, m), 3.80−3.58 (3H, m), 3.55−3.46 (1H, m), 3.43−3.27 (1H, m),
2.35−2.18 (1H, m), 2.00−1.85 (1H, m), 1.51 (9H, s), 0.97 (9H, s), 0.93
(9H, s), 0.12 (6H, s), 0.08 (6H, s). 13C NMR (75 MHz, CDCl3):
δ 159.1, 154.2, 154.1, 145.4, 145.0, 143.3, 143.2, 137.03, 136.99, 128.6,
127.9, 127.5, 117.7, 117.5, 112.7, 110.4, 110.2, 79.5, 79.2, 77.6, 77.2,
76.7, 70.0, 65.6, 65.5, 65.0, 62.8, 61.5, 47.2, 46.7, 45.7, 32.8, 31.8, 28.8,
26.2, 26.1, 18.7, 18.4, −4.9, −5.1. MS (m/z) calcd for C31H52NO3Si2
[M − Boc + H]+ 542.4, found 542.4 (−Boc). Rf 0.20 (EtOAc:toluene
(1:40)); [α]35D +3.2° (c = 0.50, abs EtOH).
111.3, 80.7, 69.7, 67.2, 66.2, 65.4, 48.1, 47.4, 33.1, 28.7, 22.8, 10.8. MS
(m/z) calcd for C16H24NO5 [M − tBu + H]+ 310.2, found 310.2. Rf 0.37
(EtOAc:heptane (3:1)); [α]23D +23.9° (c = 0.31, abs EtOH).
(2S,3R)-tert-Butyl 3-(3-(Benzyloxy)-5-(hydroxymethyl)phenyl)-2-
(hydroxymethyl)pyrrolidine-1-carboxylate (9c). Pyrrolidine 8c (967 g,
1.51 mmol, 1.00 equiv) was dissolved in dry THF (15 mL) in a dry vial
and 1 M TBAF (6 mL, 6 mmol, 3.97 equiv) added. The mixture was left
to stir at rt for 18 h. The mixture was quenched using 50% satd NaHCO3
(50 mL) and transferred to a separation funnel containing EtOAc
(50 mL). The aqueous phase was extracted with EtOAc (2 × 50 mL),
and the combined organic phases were washed with brine (75 mL),
dried over MgSO4, filtered, concentrated in vacuo, and purified using
DCVC (dia = 4 cm, 30 mL fractions, 0−100% EtOAc in heptane) to
yield diol 9c (572 mg, 92%) as a clear, colorless oil. 1H NMR (300 MHz,
CDCl3): δ 7.45−7.28 (5H, m), 6.88 (1H, m), 6.85 (1H, m), 6.79 (1H, m),
5.09 (1H, m), 5.06 (2H, s), 4.65 (2H, s), 3.95 (1H, m), 3.90−3.67
(3H, m), 3.61 (1H, dd, J = 11, 7 Hz), 3.34 (1H, m), 2.87 (1H, m), 2.14
(1H, m), 2.08−1.89 (2H, m), 1.51 (9H, s). 13C NMR (75 MHz,
DMSO-d6): δ 158.3, 153.6, 153.2, 145.0, 144.8, 144.2, 137.0, 128.3, 127.7,
127.5, 117.4, 111.8, 110.4, 78.5, 78.4, 69.0, 65.5, 62.8, 60.8, 60.7, 46.0,
45.8, 45.3, 44.5, 31.2, 30.5, 28.2. MS (m/z) calcd for C20H24NO5
(2S,3R)-tert-Butyl 3-(3-([1,1′-Biphenyl]-3-ylmethoxy)-5-(((tert-
butyldimethylsilyl)oxy)methyl)-phenyl)-2-(((tert-butyldimethylsilyl)-
oxy)methyl)pyrrolidine-1-carboxylate (8d). Lactam 7d (1.77 g,
2.42 mmol, 1.00 equiv) was dissolved in dry THF (20 mL) and 1 M
BH3·THF complex (25 mL, 25 mmol, 10.3 equiv) added over the course
of 5 min. The mixture was refluxed under an atmosphere of nitrogen for
20 h. The mixture was cooled to 0 °C, THF (40 mL) added, and H2O
(6 mL) added dropwise over the course of 15 min. NaOH (2 M, 30 mL)
was added dropwise over the course of 15 min and H2O2 (30%, 10 mL)
over the course of 15 min (organic/aqueous ratio important). After
5 min, the mixture was removed from the ice bath and left to stir at rt for
1 h. The mixture was poured into satd NaHCO3 (100 mL) and EtOAc
(75 mL). After separation, the aqueous phase was extracted with EtOAc
(2 × 75 mL) and the combined organic phases were washed with brine
(100 mL), dried over MgSO4, filtered, concentrated in vacuo, and
purified using DCVC (dia = 4 cm, 30 mL fractions, 0−2% EtOAc
in PhMe) to yield 8d (887 mg, 51%) as a clear, colorless oil. 1H NMR
(300 MHz, CDCl3): δ 7.72−7.55 (4H, m), 7.52−7.33 (5H, m), 6.91
(1H, m), 6.84−6.78 (2H, m), 5.14 (2H, s), 4.74 (2H, s), 4.08 (0.5H, dd,
J = 10, 4 Hz), 3.90 (0.5H, m), 3.86−3.62 (3H, m), 3.55 (1H, m), 3.38
(1H, m), 2.28 (1H, m), 1.94 (1H, m), 1.53 (9H, s), 0.99 (9H, s), 0.95
(9H, s), 0.14 (6H, s), 0.10 (6H, s). 13C NMR (75 MHz, CDCl3):
δ 159.1, 154.23, 154.15, 145.4, 145.0, 143.34, 143.26, 141.6, 140.9,
137.54, 137.49, 129.0, 128.8, 127.4, 127.2, 126.8, 126.44, 126.35, 117.8,
117.6, 112.8, 110.3, 110.1, 79.5, 79.2, 70.0, 65.6, 65.5, 65.0, 62.8, 61.5,
47.2, 46.7, 45.7, 32.8, 31.8, 28.8, 26.2, 26.1, 18.6, 18.4, −4.9, −5.1. MS
(m/z) calcd for C37H56NO3Si2 [M − Boc + H]+ 618.4, found 618.4.
Rf 0.21 (EtOAc:toluene (1:40)); [α]35D +1.9° (c = 0.67, abs EtOH).
(2S,3R)-tert-Butyl 3-(2,2-Dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2-
(hydroxymethyl)-pyrrolidine-1-carboxylate (9a). The protected alco-
hol (448 mg, 0.94 mmol, 1.0 equiv) was dissolved in dry THF (9 mL)
under an atmosphere of nitrogen and 1 M TBAF in THF (2.8 mL,
736 mg, 2.81 mmol, 3.0 equiv) was added at rt. The reaction mixture was
stirred for 2 h, whereafter H2O (20 mL) and satd NaHCO3 (20 mL)
were added, and following extracted with EtOAc (3 × 30 mL).
The combined organic phases were dried over anhydrous Na2SO4, filtered,
and evaporated in vacuo to dryness. Purified by DCVC (15−35% EtOAc
in heptane), followed by drying in high vacuum overnight, afforded the
desired alcohol as a colorless, viscous oil, which crystallized to a white
solid (295 mg, 87%). 1H NMR (CDCl3): δ 7.02 (1H, dd, J = 8.4, 2.3 Hz),
6.84 (1H, bs), 6.76 (1H, d, J = 8.3 Hz), 5.13 (1H, bd, J = 8.0 Hz),
4.82 (2H, s), 3.86 (1H, t, J = 7.8 Hz), 3.73 (2H, t, J = 9.4 Hz), 3.64−3.57
(1H, m), 3.33 (1H, dt, J = 10.6, 6.3 Hz), 2.84−2.76 (1H, m), 2.15−2.08
(1H, m), 1.99−1.85 (1H, m), 1.55 (6H, s), 1.51 (9H, s). 13C NMR
(CDCl3): δ 156.7, 150.1, 132.2, 127.2, 123.5, 119.4, 117.2, 99.5, 80.5,
67.2, 66.0, 60.9, 47.3, 47.1, 33.1, 28.5, 24.8, 24.7. MS (m/z) calcd for
C16H22NO5 [M − tBu + H]+ 308.2, found 308.1. [α]25D +14.2° (c = 0.86,
EtOH); mp 110−112 °C.
t
[M − Bu + H]+ 358.2, found: 358.2. Rf 0.42 (EtOAc:heptane (3:1));
[α]35D +12.3° (c = 0.44, abs EtOH).
(2S,3R)-tert-Butyl 3-(3-([1,1′-Biphenyl]-3-ylmethoxy)-5-
(hydroxymethyl)phenyl)-2-(hydroxymethyl)-pyrrolidine-1-carboxy-
late (9d). 8d (800 g, 1.11 mmol, 1.00 equiv) was dissolved in dry THF
(15 mL) in a dry vial and 1 M TBAF (5.00 mL, 5.00 mmol, 4.50 equiv)
added. The mixture was left to stir at rt for 18 h. The mixture was
quenched using phosphate buffer (50 mL, pH 7) and transferred to a
separation funnel containing EtOAc (50 mL). The aqueous phase was
extracted with EtOAc (2 × 50 mL), and the combined organic phases
was washed with brine (50 mL), dried over MgSO4, filtered,
concentrated in vacuo, and purified using DCVC (dia = 4 cm, 30 mL
fractions, 0−90% EtOAc in heptane) to yield diol 9d (512 mg, 94%) as a
clear, colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.60−7.53 (4H, m),
7.50−7.32 (5H, m), 6.91 (1H, m), 6.86 (1H, s), 6.81 (1H, m), 5.24
(1H, m), 5.10 (2H, s), 4.63 (2H, s), 3.96 (1H, m), 3.65 (2H, m), 3.63
(1H, dd, J = 11, 7 Hz), 3.34 (1H, m), 3.00−2.60 (2H, m), 2.14 (1H, m),
1.97 (1H, m), 1.51 (9H, s). 13C NMR (75 MHz, CDCl3): δ 159.2, 156.7,
143.2, 142.5, 141.5, 140.8, 137.3, 129.0, 128.8, 127.4, 127.2, 126.8, 126.5,
126.4, 118.5, 113.7, 111.3, 80.7, 70.1, 67.0, 65.9, 64.9, 47.9, 47.2, 32.9, 28.6.
MS (m/z) calcd for C26H28NO5 [M − tBu + H]+ 434.2, found 434.2. Rf
0.39 (EtOAc:heptane (3:1)); [α]35D +10.2° (c = 0.53, abs EtOH).
(2S,3R)-1-(tert-Butoxycarbonyl)-3-(2,2-dimethyl-4-oxo-4H-benzo-
[d][1,3]dioxin-6-yl)pyrrolidine-2-carboxylic Acid (10a) and (2S,3R)-1-
(tert-Butoxycarbonyl)-3-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-
pyrrolidine-2-carboxylic Acid (11). To an ice-cooled mixture of the
protected alcohol 9a (150 mg, 0.413 mmol, 1.0 equiv) dissolved in
CH3CN (2.5 mL) and EtOAc (2.5 mL) was added dropwise NaIO4
(883 mg, 4.13 mmol, 10.0 equiv) and RuCl3·H2O (4 mg, 0.02 mmol,
0.04 equiv) dissolved in H2O (4 mL). The reaction was stirred at 0 °C
for 1.5 h. The brownish reaction mixture was filtered through a plug of
Celite and washed with EtOAc (15 mL). The filtrates weretransferred to a
separating funnel, and the organic layer was isolated. The aqueous layer
was extracted with EtOAc (2 × 15 mL), and the combined organic phases
were washed with brine (25 mL) and dried over anhydrous Na2SO4. The
crude product was isolated as a dark-brown oil by evaporation in vacuo
(179 mg). Purification by DCVC (5−25% EtOAc in heptane containing
1% AcOH) afforded compound 10a and 11, respectively. For 10a:
White foam (36 mg, 22%). 1H NMR (CDCl3): δ 7.88−7.84 (1H, m),
(2S,3R)-tert-Butyl 2-(Hydroxymethyl)-3-(3-(hydroxymethyl)-5-
propoxyphenyl)pyrrolidine-1-carboxylate (9b). Pyrrolidine 8b
(1.30 g, 2.19 mmol, 1.00 equiv) was dissolved in dry THF (12 mL) in
a dry vial and 1 M TBAF (8.80 mL, 8.80 mmol, 4.02 equiv) added. The
mixture was left to stir at rt for 18 h. The mixture was quenched using
50% satd NaHCO3 (50 mL) and transferred to a separation funnel
N
J. Med. Chem. XXXX, XXX, XXX−XXX