Journal of Medicinal Chemistry
ARTICLE
5.04 (s, 2H), 5.06-5.12 (m, 2H), 5.74-5.83 (m, 1H), 6.90 (d, J = 11.2 Hz,
2H), 7.08 (d, J = 11.2 Hz, 2H), 7.30-7.44 (m, 5H). 13C NMR (90 MHz,
CDCl3) δ 28.5, 40.7, 53.8, 70.2, 79.4, 114.8, 114.9, 127.6, 128.0, 128.7, 130.0,
130.7, 137.3, 138.4, 155.4, 157.7. HRMS calcd for C22H27NO3 (Mþ þ Na) =
376.1889, found 376.1879.
(R)-N-(tert-Butoxycarbonyl)-3-amino-4-(2-naphtyl)-1-butene (10e).
Prepared according to the general procedure and was purified by flash
chromatography (n-hexane/EtOAc = 20/1) to give 10e (80%) as a
colorless solid; mpt 104 °C; [R]D25 = -42.46 (c = 0.32). 1H NMR (360
MHz, CDCl3) δ 1.38 (s, 9H), 2.97-3.01 (m, 2H), 4.50 (br s, 1H), 5.07-
5.14 (m, 2H), 5.79-5.87 (m, 1H), 7.33 (d, J = 9.7 Hz, 1H), 7.40-7.47
(m, 2H), 7.63 (s, 1H), 7.76-7.82 (m, 3H). 13CNMR(90MHz, CDCl3) δ
28.5, 41.9, 53.5, 115.1, 125.7, 126.2, 127.8, 127.8, 128.1, 128.2, 128.3, 132.5,
133.7, 135.2, 138.3, 155.4, tert-butyl carbon not observed. HRMS calcd
for C19H23NO2 (Mþ þ Na) = 320.1624, found 320.1620.
to 70%. HPLC purification of the mixture provided the individual
diastereomers.
(2R,3R)-N-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-phenyl Buta-
noic Acid (12b). Mp 148 °C. 1H NMR (360 MHz, DMSO-d6) δ 1.27 (s,
9H), 2.66-2.68 (m, 2H), 3.92-4.00 (m, 2H), 6.66 (d, J = 9.0 Hz, 1H,
NH), 7.16-7.26 (m, 5H). 13C NMR (90 MHz, DMSO-d6) δ 28.1, 34.9,
54.5, 72.6, 77.5, 125.8, 127.9, 129.0, 139.2, 154.9, 173.9.
(2S,3R)-N-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-phenyl Buta-
1
noic Acid (13b). Mp 126 °C. H NMR (360 MHz, DMSO-d6) δ 1.30
(s, 9H), 2.66-2.71 (m, 1H), 2.78-2.83 (m, 1H), 3.96-4.03
(m, 1H), 5.14 (br s, 1H), 6.37 (d, J = 9.4 Hz, 1H, NH), 7.17-7.30 (m,
5H), 12.5 (s, 1H). 13C NMR (90 MHz, DMSO-d6) δ 27.7, 28.1, 37.5, 54.7,
70.4, 77.8, 126.0, 128.1, 129.1, 138.6, 154.8, 174.0.
(2R,3R)-N-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-(p-methyloxy-
phenyl)-butanoic Acid (12c). 1H NMR (360 MHz, DMSO-d6) δ 1.28
(s, 9H), 2.60-2.62 (m, 2H), 3.70 (s, 3H), 3.36-3.88 (m, 1H), 3.99-4.0
(m, 1H), 6.53 (d, J = 8.6 Hz, 1H, NH), 6.81 (d, J = 8.6 Hz, 2H), 7.08
(d, J= 8.6 Hz, 2H). 13C NMR (90 MHz, DMSO-d6) δ28.1, 33.9, 54.7, 54.9,
72.5, 77.5, 107.8, 113.4, 129.9, 130.9, 154.9, 157.5, 174.0.
(2S,3R)-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-(p-methyloxy-
phenyl)-butanoic Acid (13c). Mp 55 °C. 1HNMR(360MHz, DMSO-d6)
δ 1.33 (s, 9H), 2.632.65 (m, 1H), 2.71-2.73 (m, 1H), 3.72 (s, 3H),
3.84-3.94 (m, 2H), 6.32 (d, J = 9.36 Hz, 1H, NH), 6.84 (d, J =
8.6 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H). 13C NMR (90 MHz, DMSO-
d6) δ 27.8, 28.2, 36.6, 54.9, 55.0, 70.3, 77.8, 113.7, 130.1, 130.5,
154.9, 157.7, 174.1. HRMS calcd for C16H24NO6 (Mþ þ H)
326.1598, found 326.1599.
(2R,3R)-N-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-(p-benzyloxy
phenyl)-butanoic Acid (12d). Mp 129 °C. 1H NMR (360 MHz, DMSO-
d6) δ1.27 (s, 9H), 2.60-2.61 (m, 2H), 3.85-3.86 (m, 1H), 3.96-3.99 (m,
1H), 5.04 (s, 2H), 6.61 (d, J = 8.6 Hz, 1H, NH), 6.88 (d, J = 8.3 Hz, 2H),
7.08 (d, J = 8.3 Hz, 2H), 7.31-7.43 (m, 5H). 13C NMR (90 MHz, DMSO-
d6) δ 28.1, 33.9, 54.7, 69.1, 72.5, 77.5, 114.3, 127.5, 127.7, 128.3, 130.0,
131.2, 137.3, 155.0, 156.6, 174.0.
(R)-N-(tert-Butoxycarbonyl)-3-amino-4-(p-phenylphenyl)-1-butene
10f). Prepared according to the general procedure and was purified by
flash chromatography (n-hexane/EtOAc = 20/1) to give 10f (67%) as a
colorless solid. 1H NMR (360 MHz, CDCl3) δ 1.40 (s, 9H), 2.88 (d, J =
5.8 Hz, 2H), 4.47 (br s, 2H), 5.09-5.16 (m, 2H), 5.79-5.88 (m, 1H),
7.24-7.59 (m, 9H). 13C NMR (90 MHz, CDCl3) δ 28.6, 41.4, 115.0,
127.2, 127.3, 127.4, 129.0, 130.2, 136.8, 138.3, 139.6, 141.1, 155.4.
(R)-N-(tert-Butoxycarbonyl)-3-amino-5,5-diphenyl-1-pentene (10g).
Prepared according to the general procedure and was purified by flash
chromatography (n-hexane/EtOAc = 20/1) to give 10g (78%) as a
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1
colorless solid; mp 98 °C; [R]D = -56.89 (c = 0.58, CHCl3). H
NMR (360 MHz, CDCl3) δ 1.36 (s, 9H), 3.97 (d, J = 9.4 Hz, 2H), 4.39
(br s, 1H), 4.99 (br s, 1H), 5.03-5.16 (m, 2H), 5.71-5.80 (m, 1H), 7.15-
7.30 (m, 10H). 13C NMR (90 MHz, CDCl3) δ 28.5, 55.4, 57.0, 115.5,
126.8, 127.0, 128.7, 128.7, 128.8, 128.9, 137.7, 141.8, 155.5, tert-butyl carbon
not observed. HRMS calcd for C21H25NO2 (Mþ þ Na) = 346.1783, found
346.1784.
(R)-N-(tert-Butoxycarbonyl)-3-amino-4-propyl-1-butene (10h).
Prepared according to the general procedure and was purified by flash
chromatography (n-hexane/EtOAc = 20/1) to give 10h (65%) as an
(2S,3R)-N-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-(p-benzyl-
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1
oxyphenyl)-butanoic Acid (13d). Mp 52 °C; [R]D = þ56.84
oily liquid. H NMR (360 MHz, CDCl3) δ 0.89 (t, 3H, J = 6.8 Hz),
1
(c = 0.19, MeOH). H NMR (360 MHz, DMSO-d6) δ 1.31 (s, 9H),
1.27-1.33 (m, 4H), 1.42-1.51 (s, 11H), 4.07 (brs, 1H), 4.53 (brs,
1H), 5.05-5.16 (m, 2H), 5.70-5.77 (m, 1H).
2.62-2.66 (m, 1H), 2.72-2.74 (m, 1H), 3.86-3.96 (m, 2H), 5.05 (s, 2H),
6.33 (d, J = 9.4 Hz, 1H, NH), 6.93 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz,
2H), 7.31-7.44 (m, 5H). 13C NMR (90 MHz, DMSO-d6) δ 28.1, 36.6,
54.9, 69.2, 70.3, 77.8, 114.6, 127.6, 127.7, 128.4, 130.2, 130.7, 137.2, 154.9,
156.9, 174.1. HRMS calcd for C22H27NO6 (Mþ - H) = 400.1760,
found =400.1755.
(2R,3R)-N-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-(2-naphtyl)-
butanoic Acid (12e). Yield 77%; mp 154-155 °C. 1H NMR (360 MHz,
DMSO-d6) δ 1.20 (s, 9H), 2.84-2.86 (m, 2H), 4.01-4.04 (m, 2H), 6.72
(d, J = 8.6 Hz, 1H, NH), 7.34-7.47 (m, 3H), 7.66 (s, 1H), 7.79-7.86
(m, 3H).
(2S,3R)-N-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-(2-naphtyl)-
butanoic Acid (13e). Mp 113 °C; [R]D25 = þ55.18 (c = 0.54, MeOH).
1H NMR (360 MHz, DMSO-d6) δ 1.26 (s, 9H), 2.88-2.90 (m, 1H),
2.97-2.99 (m, 1H), 3.93 (s, 1H), 4.11-4.13 (m, 1H), 6.42 (d, J = 9.7 Hz,
1H, NH), 7.39-7.48 (m, 3H), 7.71 (s, 1H), 7.82-7.87 (m, 3H). 13CNMR
(90 MHz, DMSO-d6) δ 28.1, 37.7, 54.7, 70.6, 77.8, 125.3, 125.9, 127.3,
127.4, 127.4, 127.6, 127.8, 131.8, 133.1, 136.2, 154.9, 174.0. HRMS calcd for
C19H23NO5 (Mþ - H) = 344.1498, found = 344.1497.
(2R,3R)-N-(tert-Butoxycabonyl)-3-amino-2-hydroxy-4-(p-phenylphe-
nyl)-butanoic Acid (12f). 1HNMR(360MHz, DMSO-d6) δ1.27(s, 9H),
2.73 (br s, 2H), 3.95-4.03 (m, 2H), 6.71 (d, J = 8.8 Hz, 1H, NH), 7.26-
7.63 (m, 9H). 13C NMR (90 MHz, DMSO-d6) δ 27.7, 28.1, 34.5, 54.6, 72.6,
77.5, 126.2, 126.4, 127.1, 128.8, 129.6, 137.7, 138.5, 140.1, 155.0, 174.0.
(2S,3R)-N-(tert-Butoxycarbonyl)-3-amino-2-hydroxy-4-(p-phenylphe-
nyl)-butanoic Acid (13f). Mp 162-163 °C. 1H NMR (360 MHz,
DMSO-d6) δ ; 1.31 (s, 9H), 2.73-2.76 (m, 1H), 2.83-2.89
General Method for the Synthesis of R-Hydroxy-β-amino Acid. In
an oven-dried, 50 mL, single-necked, round-bottom flask equipped with
a magnetic stirring bar, rubber septum, and argon balloon was placed the
alkene (1.20 g, 4.33 mmol) in t-BuOH:H2O (12 mL, 1:1) and
methanesulfonamide (0.412 g, 4.33 mmol) was added. The reaction
mixture was cooled to 0 °C and AD-mix-R (6.54 g) was added. The
resulting mixture was stirred at 0 °C for 36 h and at room temperature
for 8 h and then quenched with solid Na2SO3 (7.0 g) and extracted with
ethyl acetate. The organic extracts were washed with NaOH (1M, 10
mL), water and brine, dried (Mg2SO4), and concentrated. The crude
diol was used as such for the next step.
The residue was dissolved in phosphate buffer (NaH2PO4, pH 6.7, 6 mL)
and MeCN (6 mL). To the solution was added 2,2,6,6-tetramethylpiperidin-
1-oxyl (TEMPO, 0.169 g, 1.07 mmol) and sodium chlorite (0.697 g, 7.71
mmol). The reaction mixture was warmed to 35 °C, and 4% aqueous sodium
hypochlorite (NaOCl) solution (0.008 g, 0.12 mmol) was added. The
mixture was stirred at this temperature for 6.5 h, and TEMPO (0.053 g, 0.34
mmol) along with 4% aqueous NaOCl solution (0.001 g, 0.02 mmol) were
added. After stirring at 35 °C for 24 h, H2O (5 mL) was added, and thepH of
the mixture was adjusted to 8.0 with 2.0 M aqueous NaOH solution. The
reaction flask was cooled to 20 °C and 6% aq sodium sulfite was added until
the solution had a pH of 9. After warming to rt for 30 min, Et2O (5 mL) was
added and the organic phase was separated. To the aqueous layer 1N HCl was
added until the pH of the solution was 3, and extracted with ethyl acetate,
washed with brine dried and concentrated to yield the R-hydroxy-β-amino
acids. The combined yields of the R-hydroxy-β-amino acids ranged from 65%
1663
dx.doi.org/10.1021/jm101227t |J. Med. Chem. 2011, 54, 1655–1666