E
A. López-Rodríguez et al.
Feature
Synthesis
1R*,4R*,5S*,6R*,7R*-Isomer 4b
1H NMR (400 MHz, CDCl3): δ = 7.40–7.29 (m, 5 H, CH Ar), 5.26–5.10
(m, 2 H, CH2Ar), 4.21–4.00 (m, 5 H, CH2CH3 + H3 + H4 + H5), 3.54 (dd,
J = 8.4, 2.8 Hz, 1 H, H1, β), 3.48 (dd, J = 8.5, 2.6 Hz, 1 H, H1, α), 2.99 (d,
J = 13.9 Hz, 1 H, H3, β), 2.89 (d, J = 14.0 Hz, 1 H, H3, α), 2.39 (dd, J = 5.7,
2.6 Hz, 1 H, H7), 2.16–2.09 (m, 1 H, H6), 1.29–1.25 (m, 3 H, CH2CH3, β),
1.19 (t, J = 7.2 Hz, 3 H, CH2CH3, α).
13C NMR (101 MHz, CDCl3): δ (major conformer = 171.5 (CO2), 157.4
(NCO2), 136.4 (C Ar), 128.4 (CH Ar), 127.9 (CH Ar), 127.4 (CH Ar), 67.8
(C4), 67.6 (CH2Ar), 64.3 (C5), 60.8 (CH2CH3), 46.3 (C3), 39.8 (C1), 26.8
(C6), 26.5 (C7), 14.1 (CH2CH3).
Yield: 151 mg (0.56 mmol, 32%); colorless oil; Rf = 0.18 (hexane/EtOAc,
1:2). The compound was assigned as 1R*,4R*,5S*,6R*,7R* due to the
absence of NOESY cross peaks between H5 and H6. NMR spectra
showed a mixture of two conformers [80% (α):20% (β)].
IR (ATR): 3431, 2985, 2921, 1704 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 4.27–4.08 (m, 6 H, 2 × CH2CH3 + H3 +
H5), 4.03 (t, J = 4.0 Hz, 1 H, H4, α), 3.97 (br s, 1 H, H4, β), 3.52 (d, J = 9.3
Hz, 1 H, H1, β), 3.42 (dd, J = 8.5, 2.6 Hz, 1 H, H1, α), 2.97 (d, J = 13.1 Hz,
1 H, H3, β), 2.86 (d, J = 14.0 Hz, 1 H, H3, α), 2.46 (br s, 1 H, C5-OH),
2.37 (br s, 1 H, C4-OH), 2.35 (dd, J = 5.8, 2.6 Hz, 1 H, H7), 2.13 (m, 1 H,
H6), 1.27 (t, J = 7.0 Hz, 3 H, CH2CH3), 1.26 (t, J = 7.1 Hz, 3 H, CH2CH3).
Anal. Calcd for C17H21NO6 (335.35): C, 60.9; H, 6.3. Found: C, 61.0; H,
6.6.
13C NMR (101 MHz, CDCl3): δ (major conformer) = 171.7 (CO2), 157.8
(NCO2), 67.8 (C4), 64.4 (C5), 61.9 (CH2CH3), 60.7 (CH2CH3), 46.2 (C3),
39.9 (C1), 26.8 (C7), 26.6 (C6), 14.5 (CH2CH3), 14.3 (CH2CH3).
Ethyl (1S*,4S*,5R*,6R*,7R*)-4,5-Dihydroxy-7-(hydroxymethyl)-2-
azabicyclo[4.1.0]heptane-2-carboxylate (6a)
To a solution of 4a (150 mg, 0.55 mmol) in THF (2.2 mL) THF was add-
ed LiBH4 (36 mg, 1.65 mmol) in portions at 0 °C and the resulting
mixture was stirred at r.t. overnight. Then, acidic Amberlite was add-
ed, the mixture diluted with MeOH, and filtered to give 89 mg (0.38
mmol, 71%) of pure 6a as a colorless oil; Rf = 0.1 (EtOAc). NMR spectra
showed a mixture of two conformers [60% (α):40% (β)].
Anal. Calcd for C12H19NO6 (273.28): C, 52.7; H, 7.0. Found: C, 52.6; H,
6.8.
2-Benzyl 7-Ethyl 4,5-Dihydroxy-2-azabicyclo[4.1.0]heptane-2,7-
dicarboxylate
Following the same procedure as for 4, from 3b (400 mg, 1.33 mmol),
aq 4% OsO4 (2.69 mL, 0.26 mmol), and 4-methylmorpholine N-oxide
(230.5 mg, 1.97 mmol) in H2O (230 μL), a crude 1:1 mixture of two
diastereoisomers was obtained, which were separated after flash col-
umn chromatography (hexane/EtOAc 1:2) and characterized.
IR (ATR): 3398, 3022, 2932, 1680 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 4.24–4.09 (m, 3 H, CH2CH3 + H5), 3.63
(dd, J = 11.5, 5.8 Hz, 1 H, CHHOH), 3.58 (dd, J = 12.2, 3.8 Hz, 1 H, H3, α),
3.52 (dd, J = 12.1, 4.0 Hz, 1 H, H3, β), 3.46–3.37 (m, 1 H , H4), 3.37–
3.28 (m, 1 H, CHHOH), 3.02 (dd, J = 12.1, 10.4 Hz, 1 H, H3, β), 2.93 (dd,
J = 12.2, 10.6 Hz, 1 H, H3, α), 2.80–2.74 (m, 1 H, H1), 1.41 (m, 1 H, H6),
1.31–1.25 (m, 3 H, CH2CH3), 0.91–0.84 (m, 1 H, H7).
13C NMR (101 MHz, CD3OD): δ = 158.9 (CO2, α), 158.5 (CO2, β), 68.6
(C4, α), 68.4 (C4, β), 66.7 (C5, α), 66.5 (C5, β), 64.0 (CH2OH, β), 63.7
(CH2OH, α), 62.9 (CH2CH3, β), 62.8 (CH2CH3, α), 42.9 (C3, β), 42.3 (C3,
α), 34.0 (C1, β), 33.2 (C1, α), 27.5 (C7, α), 27.1 (C7, β), 25.5 (C6, α), 24.9
(C6, β), 15.0 (CH2CH3, α), 14.9 (CH2CH3, β).
1R*,4S*,5R*,6R*,7R*-Isomer 5a
Yield: 138 mg (0.41 mmol, 31%); yellow oil; Rf = 0.35 (hexane/EtOAc,
1:2). The product was assigned as 1R*,4S*,5R*,6R*,7R* due to detec-
tion of NOESY cross peaks between H5 and H6 and analogy with com-
pound 4a. NMR spectra showed a mixture of two conformers [80%
(α):20% (β)].
IR (ATR): 3427, 2980, 2924, 1702 cm–1
.
Anal. Calcd for C10H17NO5 (231.25): C, 51.9; H, 7.4. Found: C, 52.2; H,
7.2.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.28 (m, 5 H, CH Ar), 5.25–5.08
(m, 2 H, CH2Ar), 4.29 (br s, 1 H, H5), 4.20–4.02 (m, 2 H, CH2CH3), 3.75
(dd, J = 12.4, 4.1 Hz, 1 H, H3, α), 3.63 (dd, J = 12.4, 4.0 Hz, 1 H, H3, β),
3.55–3.46 (m, 1 H, H4), 3.44 (dd, J = 8.2, 2.5 Hz, 1 H, H1), 3.07 (t, J =
11.2 Hz, 1 H, H3, β), 3.00 (dd, J = 12.4, 10.8 Hz, 1 H, H3, α), 2.84–2.68
(m, 1 H, OH), 2.22–2.15 (m, 1 H, H6), 1.46 (dd, J = 6.1, 2.6 Hz, 1 H, H7),
1.29–1.23 (m, 3 H, CH2CH3, β), 1.19 (t, J = 7.1 Hz, 1 H, CH2CH3, α).
13C NMR (101 MHz, CDCl3): δ = 170.9 (CO2Et), 156.3 (NCO2), 136.2 (C
Ar, α), 136.0 (C Ar, β), 128.6 (CH Ar, β), 128.5 (CH Ar, α), 128.3 (CH Ar,
β), 128.1 (CH Ar, β), 128.0 (CH Ar, α), 127.5 (CH Ar, α), 67.7 (CH2Ar, β),
67.6 (CH2Ar, α), 67.1 (C4, α), 67.0 (C4, β), 64.5 (C5), 61.1 (CO2CH2CH3,
β), 61.0 (CO2CH2CH3, α), 41.9 (C3, β), 41.1 (C3, α), 37.2 (C1, β), 36.8
(C1, α), 27.9 (C6, α), 27.4 (C6, β), 26.0 (C7, α), 25.3 (C7, β), 14.1
(CH2CH3).
Ethyl (1S*,4R*,5S*,6R*,7R*)-4,5-Dihydroxy-7-(hydroxymethyl)-2-
azabicyclo[4.1.0]heptane-2-carboxylate (6b)
Following the procedure for the synthesis of 6a, from 4b (130 mg,
0.48 mmol) and LiBH4 (31 mg, 1.43 mmol), 75 mg (0.32 mmol, 72%) of
pure 6b was obtained as a colorless oil; Rf = 0.3 (EtOAc/EtOH, 9:1).
NMR spectra showed a mixture of two conformers [71% (α):29% (β)].
IR (ATR): 3391, 3020, 2936, 1685 cm–1
.
1H NMR (400 MHz, CD3OD): δ = 4.21–4.09 (m, 2 H, CH2CH3), 4.05 (dd,
J = 6.6, 4.5 Hz, 1 H, H5), 3.96–3.81 (m, 2 H, H4 + H3), 3.61 (dd, J = 11.3,
5.9 Hz, 1 H, CHHOH, α), 3.54 (dd, J = 11.3, 6.5 Hz, 1 H, CHHOH, β),
3.39–3.26 (m, 1 H, CHHOH), 2.93 (d, J = 12.8 Hz, 1 H, H3, β), 2.84 (dd,
J = 13.4, 1.5 Hz, 1 H, H3, α), 2.81 (dd, J = 8.4, 3.1 Hz, 1 H, H1, α), 2.78
(dd, J = 8.5, 3.0 Hz, 1 H, H1, β), 1.80–1.72 (m, 1 H, H7), 1.40–1.23 (m, 4
H, H6 + CH2CH3).
Anal. Calcd for C17H21NO6 (335.35): C, 60.9; H, 6.3. Found: C, 61.0; H,
6.0.
13C NMR (101 MHz, CD3OD): δ = 159.8 (CO2, α), 159.5 (CO2, β), 69.3
(C4, α), 69.2 (C4, β), 66.3 (C5, α), 66.1 (C5, β), 64.5 (CH2OH, β), 64.3
(CH2OH, α), 62.8 (CH2CH3, β), 62.7 (CH2CH3, α), 47.5 (C3, β), 47.3 (C3,
α), 36.6 (C1, β), 35.7 (C1, α), 28.2 (C7, α), 27.8 (C7, β), 22.9 (C6, α), 22.7
(C6, β), 15.0 (CH2CH3, α), 14.9 (CH2CH3, β).
1S*,4R*,5S*,6R*,7R*-Isomer 5b
Yield: 156 mg (0.47 mmol, 36%); yellow oil; Rf = 0.3 (hexane/EtOAc,
1:3). The product was assigned as 1S*,4R*,5S*,6R*,7R* due to absence
of NOESY cross peaks between H5 and H6 and analogy with com-
pound 4b. NMR spectra showed a mixture of two conformers [75%
(α):25% (β)].
Anal. Calcd for C10H17NO5 (231.25): C, 51.9; H, 7.4. Found: C, 52.1; H,
7.8.
IR (ATR): 3433, 2983, 2925, 1707 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–G