LETTER
Orthogonally Protected b-Hydroxy-a-,g-diamino Butyric Acids
2503
5.5 Hz, 1 H), 4.16–4.01 (m, 1 H), 3.94 (d, J = 2.0, 1 H), 3.74
(wavelength 210 nm) of the enantioselective HPLC trace,
the enantiomeric excess of the separated compounds was
99.0% (peak 1, eluting at 3.3 min) and 96.8% (peak 2,
eluting at 5.4 min). Using VCD, the absolute configuration
of peak 1 was assigned as (R,S) and that of peak 2 as (S,R)
(see the Supporting Information). Optical rotation for
peak 1: [a]D25 +93.4 (c 0.0025, EtOH); optical rotation of
peak 2: [a]D25 –22.4 (c 0.0036, EtOH).
(s, 3 H), 3.05 (t, J = 6.4 Hz, 2 H), 1.39 (s, 9 H). 13C NMR
(100 MHz, DMSO-d6, 325 K): d = 170.5, 156.4, 78.5, 71.4,
63.6, 53.2, 43.9, 28.9. HRMS (ESI): m/z [M + Na]+ calcd for
C10H18N4NaO5: 297.1175; found: 297.1170.
(18) Data for compound syn-8: 2,2-Dimethoxypropane (8.14
mL, 66.4 mmol, 14.0 equiv) and p-toluenesulfonic acid (361
mg, 1.90 mmol, 0.40 equiv) were added to a solution of syn-
7 (1.30 g, 4.74 mmol, 1.00 equiv) in acetone (35 mL) at room
temperature. The resulting mixture was stirred at that
temperature for 12 h. A saturated aqueous solution of
NaHCO3 (50 mL) was then added and the mixture was
stirred for 15 min. The acetone was removed using a stream
of N2, and dichloromethane (50 mL) was then added. The
layers were separated and the aqueous layer was extracted
with dichloromethane (3 × 50 mL). The combined organic
extracts were washed with brine (100 mL), dried over
anhydrous sodium sulfate, filtered, and concentrated in
vacuo. The crude product was purified by flash column
chromatography (ethyl acetate–heptanes, 0→20%) to afford
syn-8 (1.12 g, 75% yield) as a colorless oil. IR (neat): 2114
cm–1. 1H NMR (400 MHz, DMSO-d6, 325 K): d = 4.60 (ddd,
J = 3.0, 6.7, 8.5 Hz, 1 H), 4.33 (d, J = 3.0 Hz, 1 H), 3.76 (s,
3 H), 3.67 (dd, J = 6.7, 10.2 Hz, 1 H), 3.35 (dd, J = 8.6,
10.1 Hz, 1 H), 1.49 (s, J = 3 H), 1.41 (s, 9 H), 1.40 (s, 3 H).
13C NMR (100 MHz, DMSO-d6, 325 K): d = 169.1, 151.7,
[94.3, 94.1], [80.0, 79.6], [74.4, 74.1], 61.3, 53.4, 47.5, 28.5,
[27.0, 25.9], [25.4, 24.4]. Rotameric signals are indicated
with square brackets. HRMS (ESI): m/z [M + Na]+ calcd for
C13H22N4NaO5: 337.1488; found: 337.1475.
(21) Data for compound syn-1: A 1.00 M aqueous solution of
NaOH (2.05 mL, 2.05 mmol, 1.50 equiv) was added to a
solution of CaCl2 (2.43 g, 21.9 mmol, 16.0 equiv) in i-
PrOH–water (7:3, 45 mL). The resulting cloudy reaction
mixture was cooled to 0 °C and transferred by cannula to
intermediate syn-9 (697 mg, 1.37 mmol, 1.00 equiv). The
mixture was warmed to room temperature and stirred at that
temperature for 4 h. The reaction mixture was diluted with
water (40 mL) and dichloromethane (40 mL). The phases
were separated and the aqueous phase was acidified to pH~5
with a 1 M aqueous solution of HCl. The aqueous layer was
extracted with dichloromethane (3 × 50 mL) and the
combined organic extracts were dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The
crude product was purified by flash column chromatography
(ethyl acetate–heptanes, 0→70%) to afford syn-1 (144 mg,
75% yield) as a colorless oil. IR (neat): 1693 cm–1. 1H NMR
(400 MHz, DMSO-d6, 325 K): d = 13.0 (br, 1 H), 7.89 (d,
J = 8.0 Hz, 2 H), 7.82–7.70 (m, 2 H), 7.42 (t, J = 7.5 Hz,
2 H), 7.37–7.27 (m, 2 H), 4.56–4.41 (m, 1 H), 4.39–4.18 (m,
5 H), 3.68–3.57 (m, 1 H), 3.16 (t, J = 8.0 Hz, 1 H), 1.51 (br,
3 H), 1.41 (br, 12 H). 13C NMR (100 MHz, DMSO-d6,
325 K):
(19) Data for compound ( )-syn-9: 10% Pd/C (65.0 mg, 0.06
mmol Pd, 0.17 equiv) was added to a solution of syn-8 (1.12
g, 3.57 mmol, 1.00 equiv) in MeOH–THF (2:1, 45 mL). The
resulting mixture was hydrogenated at room temperature
using a Parr shaker (45 psi) for 5 h. The solvent was then
removed in vacuo to afford the crude product, which was
used in the next step without purification. N-(9-Fluorenyl-
methoxycarbonyloxy)succinimide (2.34 g, 6.94 mmol, 1.94
equiv) and N-methyl morpholine (550 mL, 5.00 mmol, 1.40
equiv) were added to a solution of the crude product in
dichloromethane (45 mL) at room temperature and the
resulting mixture was stirred at that temperature for 12 h.
The reaction mixture was diluted with a saturated aqueous
solution of ammonium chloride (75 mL) and the layers
were separated. The aqueous layer was extracted with
dichloromethane (3 × 75 mL), the combined organic phases
were washed with brine (100 mL), dried over anhydrous
sodium sulfate, filtered, and concentrated in vacuo. The
crude product was purified by flash column chromatography
(ethyl acetate–heptanes, 0→30%) to afford ( )-syn-9 (1.37
g, 75% yield over two steps) as a colorless oil. IR (neat):
1698 cm–1. 1H NMR (400 MHz, DMSO-d6, 325 K): d =
7.93–7.84 (m, 3 H), 7.74 (dd, J = 4.0, 8.0 Hz, 2 H), 7.42 (t,
J = 8.0 Hz, 2 H), 7.36–7.28 (m, 2 H), 4.52–4.43 (m, 1 H),
4.43–4.36 (m, 1 H), 4.35–4.20 (m, 3 H), 3.67 (s, 3 H), 3.65–
3.57 (m, 1 H), 3.17 (t, J = 8.0 Hz, 1 H), 1.50 (s, 3 H), 1.40
(br, 12 H).13C NMR (100 MHz, DMSO-d6, 325 K): d =
170.6, 156.8, 151.7, 144.2, 144.2, 141.2, 141.2, 128.1,
127.5, 127.5, 125.8, 125.8, 120.6, 120.6, [93.6, 93.3], [79.8,
79.4], [73.0, 72.6], 66.4, 55.5, 52.7, [47.8, 47.6], 47.0, 28.5,
[27.3, 26.1], [25.5, 24.6]. Rotameric signals are indicated
with square brackets. HRMS (ESI): m/z [M + Na]+ calcd for
C28H34N2O7Na: 533.2264; found: 533.2244.
d = 171.6, 156.9, 151.7, 144.2, 144.2, 141.2, 141.1, 128.1,
127.5, 127.5, 125.9, 125.8, 120.6, 120.6, [93.5, 93.3], [79.8,
79.4], [73.2, 72.8], 66.4, [55.4, 55.4], [47.9, 47.7], 47.0,
28.5, [27.3, 26.1], [25.5, 24.5]. Rotameric signals are
indicated with square brackets. The following signals
coalesced at 343 K: 13C NMR (100 MHz, DMSO-d6, 343 K):
d = 171.1, 156.5, 151.6, 144.0, 144.0, 141.0, 141.0, 127.8,
127.2, 127.2, 125.4, 125.4, 120.2, 120.2, 93.2, 79.4, 72.9,
66.3, 55.5, 47.6, 47.0, 28.3, 26.5, 24.9. HRMS (ESI): m/z [M
+ Na]+ calcd for C27H32N2NaO7: 519.2107; found: 519.2104.
Optical rotation for syn-1 and ent-syn-1: [a]D25 –5.00 (c 0.01,
MeOH), +5.08 (c 0.01, MeOH). The absolute configuration
of each enantiomer was not determined.
(22) Coleman, R. S.; Felpin, F.-X.; Chen, W. J. Org. Chem. 2004,
69, 7309.
(23) Data for dihydroxylation product of trans-4: Synthesized
using the same procedure used for compound cis-4. IR
(neat): 3442, 2975, 1741, 1664 cm–1. 1H NMR (400 MHz,
DMSO-d6, 353 K): d = 7.14 (dm, J = 8.6 Hz, 2 H), 6.89 (dm,
J = 8.6 Hz, 2 H), 4.86 (d, J = 7.0 Hz, 1 H), 4.60 (d, J =
7.3 Hz, 1 H), 4.41 (d, J = 15.4 Hz, 1 H), 4.36 (d, J = 15.4 Hz,
1 H), 4.03 (m, 1 H), 3.99 (dd, J = 7.0, 2.7 Hz, 1 H), 3.74 (s,
3 H), 3.65 (s, 3 H), 3.25 (dd, J = 14.2, 5.3 Hz, 1 H), 3.12 (dd,
J = 14.2, 7.4 Hz, 1 H), 1.41 (s, 9 H). 13C NMR (100 MHz,
DMSO-d6, 353 K): d = 172.4, 158.1, 154.9, 130.3, 128.1,
113.6, 78.6, 71.6, 70.1, 54.8, 51.0, 49.9, 48.7, 27.7. HRMS
(ESI): m/z [M + Na]+ calcd for C18H27NNaO7: 392.1685;
found: 392.1687.
(24) The separation was carried out on a 0.5 gram scale. Column:
Chiralcel OD-H; dimension: 10 × 250 mm; mobile phase:
CO2/methanol (90:10); flow rate: 10 mL/min; dissolving
solvent: methanol (3 mL). As judged by the UV spectrum
(wavelength 210 nm) of the enantioselective HPLC trace,
the enantiomeric excess of the separated compounds was
99.1% (peak 1, eluting at 3.7 min) and 95.1% (peak 2,
eluting at 6.4 min). Using VCD, the absolute configuration
(20) The separation was carried out on a 1.5 gram scale. Column:
Chiralpak AD-H; dimension: 21 × 250 mm; mobile phase:
CO2/methanol (85:15); flow rate: 50 mL/min; dissolving
solvent: methanol (100 mL). As judged by the UV spectrum
Synlett 2011, No. 17, 2499–2504 © Thieme Stuttgart · New York