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DOI: 10.1055/s-0030-1260331
Stereoselective Synthesis of Orthogonally Protected β-Hydroxy-α-,γ-diamino Butyric Acids
Publikationsverlauf
Publikationsdatum:
27. September 2011 (online)
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Abstract
A synthesis of all four stereoisomers of the unnatural amino acid β-OH Dab (α,γ-diamino butyric acid) in orthogonally protected form is described. The synthetic strategy relies on a three-step sequence comprising stereoselective dihydroxylation, sulfite formation, and regioselective sulfite opening with azide to build the densely functionalized carbon skeleton.
Key words
unnatural amino acids - butyric acid derivatives - natural products - novel pharmaceuticals - stereoselective synthesis
- Supporting Information for this article is available online:
- Supporting Information
- For articles on unnatural amino acids, see:
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References and Notes
Data for compound
cis
-4: Lindlar
catalyst (5 wt% Pd, 0.50 g, 0.03 equiv) was added to a
solution of 3 (12.0 g, 36.0 mmol, 1.00
equiv) in ethyl acetate (720 mL) at room temperature and the resulting
mixture was hydrogenated
(1 atm) for 3 h at that temperature.
The mixture was then filtered and concentrated in vacuo. The crude product was purified by flash
column chromatography (petrol-ethyl acetate, 35:100) to
afford cis-4 (8.69
g, 72%) as a colorless oil. IR (neat): 1719, 1689 cm-¹. ¹H
NMR (400 MHz, DMSO-d
6, 325 K): δ = 7.16 (d, J = 8.6 Hz, 2 H),
6.90 (d, J = 8.6 Hz, 2 H),
6.13 (br, 1 H), 5.83 (d, J = 11.7 Hz,
1 H), 4.32 (s, 2 H), 4.23 (br, 2 H),
3.73 (s, 3 H), 3.61 (s, 3 H), 1.40 (s, 9 H). ¹³C NMR
(100 MHz, DMSO-d
6, 325 K): δ = 165.9,
158.7, 148.0, 147.6, 130.1, 129.01, 114.1, 79.4, 78.5, 74.8, 55.2,
51.3, 45.3, 28.2. HRMS (ESI): m/z [M + Na]+
calcd for C18H25NNaO5:
358.1630; found: 358.1612.
Data for the dihydroxylation
product of
cis
-4:
N-Methylmorpholine-N-oxide (4.54 g, 38.8 mmol, 2.00 equiv)
and osmium tetroxide (2.5 wt% in t-butanol,
1.04 mmol, 0.10 equiv) were added to a solution of cis-4 (6.50 g, 19.4 mmol, 1.00 eq) in acetone-water
(1:1, 195 mL) at room temperature and the resulting reaction mixture
was stirred at that temperature for 5 h. The acetone was then removed using
a nitrogen stream. A saturated aqueous solution of NaS2O3 (650
mL) and ethyl acetate (100 mL) were added and the resulting mixture
was stirred for 1 h at room temperature. The phases were separated
and the aqueous phase was extracted with ethyl acetate (3 × 300
mL). The combined organic phases were washed with brine (300 mL), dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
The crude product was purified by flash column chromatography (ethyl
acetate-heptanes, 0→50%) to afford the
title compound (6.20 g, 87% yield)
as a colorless
oil. IR (neat): 3429, 2976, 1738, 1688 cm-¹.
¹H
NMR (400 MHz, DMSO-d
6, 353 K): δ = 7.12 (dm, J = 8.7 Hz, 2 H),
6.88 (dm, J = 8.7 Hz,
2 H), 5.18 (d, J = 4.2 Hz, 1 H),
4.78 (d, J = 4.6 Hz,
1 H), 4.45 (d, J = 15.5 Hz,
1 H), 4.30 (d, J = 15.5 Hz,
1 H), 3.99 (m, 1 H), 3.96 (m, 1 H), 3.74 (s,
3 H), 3.63 (s, 3 H), 3.28 (dd, J = 14.5,
4.1 Hz, 1 H), 3.09 (dd, J = 14.5,
7.9 Hz, 1 H), 1.40 (s, 9 H). ¹³C
NMR (100 MHz, DMSO-d
6, 353 K): δ = 172.0,
158.1, 155.0, 130.3, 128.0, 113.6, 78.4, 73.1, 70.8, 54.8, 50.7,
49.8, 48.0, 27.7. HRMS (ESI): m/z [M + Na]+ calcd
for C18H27NNaO7: 392.1685; found:
392.1679.
The separation was carried out on a 1 gram scale. Column: Chiralpak AD-H; dimension: 21 × 250 mm; mobile phase: CO2/ethanol (85:15); flow rate: 65 mL/min; dissolving solvent: ethanol (60 mL). As judged by the UV spectrum (wavelength 210 nm) of the enantioselective HPLC trace, the enantiomeric excess of the separated compounds was 99.9% (peak 1, eluting at 4.3 min) and 98.0% (peak 2, eluting at 6.9 min). Using VCD, the absolute configuration of ‘peak 1’ was assigned as (R,R) and that of ‘peak 2’ as (S,S) (see the Supporting Information). Optical rotation for peak 1: [α]D ²5 -18.9 (c 0.0047, EtOH); optical rotation of peak 2: [α]D ²5 +21.00 (c 0.0054, EtOH).
12
Data for compound
anti
-5:
Pyridine (1.43 mL, 17.6 mmol, 4.00 equiv) was added to an ice-cold
solution of the dihydroxylation product (see reference 10) and the
resulting mixture was stirred at that temperature for 5 min.
Thionyl chloride (787 mg, 6.62 mmol, 1.50 equiv) was then added
at
0 ˚C and the reaction mixture was stirred at room temperature
for 4 h. Ice water (20 mL) and ethyl acetate (20 mL) were
then added, the layers were separated and the organic phase was
washed with a saturated aqueous solution of CuSO4 (3 × 20
mL) and brine (20 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-5 (1.80
g, 99% yield) as a colorless oil.
IR (neat): 2974, 1762, 1690 cm-¹. ¹H
NMR (400 MHz, DMSO-d
6, 323 K):
δ = 7.15
(dm, J = 8.5 Hz, 2 H),
6.90 (dm, J = 8.5 Hz,
2 H), 5.66 (d, J = 6.1 Hz,
1 H), 5.31 (ddd, J = 9.5,
6.1, 2.7 Hz, 1 H), 4.44 (d, J = 15.4 Hz,
1 H), 4.33 (d, J = 15.4 Hz,
1 H), 3.73 (s, 3 H), 3.70 (s, 3 H), 3.53
(br m, 1 H), 3.24 (dd, 15.0, 9.5 Hz, 1 H),
1.40 (s, 9 H). Compound anti-5 began decomposing at 323 K and therefore
the ¹³C NMR spectrum could not be assigned
with the data collected. HRMS (ESI): m/z [M + 18]+
calcd for C18H25NNaO8S:
438.1199; found: 438.1191.
Data for compound syn -6: Sodium azide (2.46 g, 37.8 mmol, 2.50 equiv) was added to a solution of syn-5 (6.30 g, 15.2 mmol, 1.00 equiv) in DMF (75 mL) at room temperature and the resulting reaction mixture was stirred at 45 ˚C for 12 h. Water (200 mL) and ethyl acetate (100 mL) were then added and the biphasic mixture was stirred for 2 h. The layers were separated and the organic phase was washed with a saturated aqueous solution of NaHCO3 (2 × 100 mL), water (2 × 100 mL), and 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-6 (2.10 g, 35% yield) as a light-yellow oil. IR (neat): 3409, 2975, 2113, 1746, 1665 cm-¹. ¹H NMR (400 MHz, DMSO-d 6, 333 K): δ = 7.15 (dm, J = 8.6 Hz, 2 H), 6.90 (dm, J = 8.6 Hz, 2 H), 5.50 (d, J = 5.6 Hz, 1 H), 4.40 (d, J = 14.4 Hz, 1 H), 4.33 (d, J = 14.4 Hz, 1 H), 4.29 (m, 1 H), 3.88 (d, J = 2.2 Hz, 1 H), 3.74 (s, 3 H), 3.73 (s, 3 H), 3.28 (dd, J = 14.1, 5.8 Hz, 1 H), 3.13 (dd, J = 14.1, 7.1 Hz, 1 H), 1.41 (s, 9 H). ¹³C NMR (100 MHz, DMSO-d 6, 333 K): δ = 169.1, 158.3, 154.9, 130.0, 128.3, 113.7, 78.9, 70.0, 63.1, 54.8, 52.1, 50.0, 49.2, 27.8. HRMS (ESI): m/z [M + 18]+ calcd for C18H26N4NaO6: 417.1750; found: 417.1747.
15The reaction of sulfite anti-5 with sodium azide was accompanied by formation of two by-products, believed to arise from elimination of the cyclic sulfite and subsequent condensation. These by-products were tentatively assigned as A (formed in 24% yield) and B (formed in 12% yield) as depicted in Figure [²] (see the Supporting Information for spectral data). The analogous reaction of sulfite syn-5 with sodium azide was relatively more efficient.
![](https://www.thieme-connect.de/media/synlett/201117/s030_f2.gif)
Figure 2
The following two dimensional NMR spectroscopic experiments were used to determine the connectivity of syn-6: Heteronuclear Multiple Bond Correlation (HMBC), Correlation Spectroscopy (COSY), and Heteronuclear Single Quantum Coherence (HSQC). Particularly, the HMBC experiment showed correlations from the proton signal of the methine group with the attached azide (¹H shift: δ = 3.8 ppm) to both the ester carbon (¹³C shift: δ = 169.1 ppm) and the methine carbon with the attached hydroxyl group (¹³C shift: δ = 70.0 ppm), thus establishing its position between these two groups.
17Data for compound syn -7: A solution of cerium ammonium nitrate (CAN; 20.7 g, 37.8 mmol, 3.20 equiv) in distilled water (75 mL) was added slowly to a solution of syn-6 (4.65 g, 11.8 mmol, 1.00 equiv) in acetonitrile (188 mL) at room temperature. The resulting mixture was stirred at that temperature for 20 min. The reaction mixture was then diluted with water (360 mL) and ethyl acetate (180 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (2 × 75 mL). The combined organic phases were washed with distilled water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (ethyl acetate-heptanes, 0→40%) to afford syn-7 (2.43 g, 75% yield) as a colorless oil. IR (neat): 3372, 2113, 1743, 1685 cm-¹. ¹H NMR (400 MHz, DMSO-d 6, 325 K): δ = 6.94 (br, 1 H), 5.57 (d, J = 5.5 Hz, 1 H), 4.16-4.01 (m, 1 H), 3.94 (d, J = 2.0, 1 H), 3.74 (s, 3 H), 3.05 (t, J = 6.4 Hz, 2 H), 1.39 (s, 9 H). ¹³C NMR (100 MHz, DMSO-d 6, 325 K): δ = 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.
18Data 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-d 6, 325 K): δ = 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-d 6, 325 K): δ = 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.
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 µL, 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-d
6, 325 K): δ = 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-d
6, 325 K): δ = 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.
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 (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: [α]D ²5 +93.4 (c 0.0025, EtOH); optical rotation of peak 2: [α]D ²5 -22.4 (c 0.0036, EtOH).
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-d
6, 325 K): δ = 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-d
6, 325 K):
δ = 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-d
6, 343
K): δ = 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: [α]D
²5 -5.00
(c 0.01, MeOH), +5.08 (c 0.01, MeOH). The absolute configuration of
each enantiomer was not determined.
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-d 6, 353 K): δ = 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-d 6, 353 K): δ = 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.
24The 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 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: [α]D ²5 -37.9 (c 0.00073, EtOH); optical rotation of peak 2: [α]D ²5 +28.9 (c 0.0024, EtOH).
25The separation was carried out on a 3.5 gram scale. Column: Chiralpak AD-H; dimension: 10 × 250 mm; mobile phase: CO2/methanol (85:15); flow rate: 50 mL/min; dissolving solvent: methanol (20 mL). As judged by the UV spectrum (wavelength 210 nm) of the enantioselective HPLC trace, the enantiomeric excess of the separated compounds was 99.4% (peak 1, eluting at 5.5 min) and 99.7% (peak 2, eluting at 6.8 min). The absolute configuration of each enantiomer was not determined.