Paper
Organic & Biomolecular Chemistry
IR νmax 3471, 2980, 2927, 2855, 1733, 1464, 1371, 1242, 1023, gel column chromatography (hexanes 100% to hexanes/EtOAc
+
+
9
51; HRMS (+ESI) m/z [M + H] calcd for C H O 331.24790, 5 : 1) afforded macrolide 4 (64 mg, 62%) as a colourless oil. R
18 33 5
f
2
0
1
found 331.24756.
= 0.60 (hexanes/EtOAc 4 : 1); [α] −43.7° (c 1.00, CHCl
3
);
H
D
Ethyl (3S,13R)-13-acetoxy-3-(methoxymethoxy)tetradecanoate NMR (500 MHz, CDCl
15). A solution of alcohol 7 (330 mg, 1.00 mmol) in dimethox- (d, J = 15.6 Hz, 1 H), 5.01 (ddq, J = 2.7, 6.3, 9.1 Hz, 1 H), 4.70
ymethane (5 mL) under argon atmosphere was treated with (d, J = 7.0 Hz, 1 H), 4.65 (d, J = 7.0 Hz, 1 H), 3.68 (m, 1 H), 3.38
(355 mg, 2.50 mmol) at room temperature. The resulting (s, 3 H), 2.58 (m, 1 H), 2.38 (m, 1 H), 1.59 (m, 2 H), 1.53 (m, 1
3
) δ 6.89 (dt, J = 7.5, 15.6 Hz, 1 H), 5.87
(
2 5
P O
1
3
suspension was stirred for 2 h and sat. aqueous NaHCO -solu- H), 1.63–1.16 (m, 18 H) ppm; C NMR (125 MHz, CDCl ) δ
3
3
tion (20 mL) was added. The solution was extracted with EtOAc 166.1, 144.2, 124.8, 95.3, 75.9, 71.1, 55.6, 36.8, 35.3, 31.8, 28.0,
3 × 50 mL), the combined organic phases were washed with 27.7, 27.4, 26.5, 26.4, 23.8, 22.0, 20.5 ppm; IR νmax 2927, 2857,
(
brine (50 mL) and dried over Na SO . Silica gel column chrom- 1715, 1656, 1457, 1355, 1318, 1264, 1147, 1098, 1033,
2
4
atography (hexanes/EtOAc 8 : 1) gave MOM-ether 15 (354 mg, 917 cm− ; HRMS (+ESI) m/z [M + H] calcd for C18
1
+
+
33 4
H O
2
0
9
+
5%) as a colourless oil. R
f
= 0.58 (hexanes/EtOAc 3 : 1); [α]
2.4° (c 1.00, CHCl ); H NMR (500 MHz, CDCl ) δ 4.88 (sex,
313.23734, found 313.23682.
(6S,16R,E)-6-(Methoxymethoxy)-16-methyloxacyclohexadec-3-
D
1
3
3
J = 6.2 Hz, 1 H), 4.66 (dd, J = 7.0, 16.4 Hz, 2 H), 4.14 (q, J = 7.1 ene-2,5-dione (16). Macrolide 4 (40 mg, 128 μmol) and SeO
2
Hz, 2 H), 3.98 (qn, J = 6.4 Hz, 1 H), 3.35 (s, 3 H), 2.55 (dd, (42.6 mg, 384 μmol) were suspended in dry 1,4-dioxane (2 mL)
J = 7.4, 15.2 Hz, 1 H), 2.45 (dd, J = 5.3, 15.2 Hz, 1 H), 2.02 (s, 3 in a sealed vessel under argon atmosphere and heated at
H), 1.63–1.22 (m, 21H), 1.20 (d, J = 6.2 Hz, 3 H) ppm; 155 °C for 55 min. The mixture was filtered over a plug of
1
3
C NMR (125 MHz, CDCl
0.5, 55.7, 40.5, 36.1, 35.0, 29.72, 29.67, 29.64, 29.62, 29.58, chromatography (hexanes/EtOAc 8 : 1) ketone 16 (32 mg, 77%)
5.5, 25.3, 21.6, 20.1, 14.4 ppm; IR νmax 2979, 2928, 2856, was obtained as yellowish solid of mp 44–47 °C. R = 0.63
3
) δ 171.7, 171.0, 96.1, 74.9, 71.2, Celite® and the filtrate was evaporated. After silica gel column
6
2
1
f
−
1
20
17
27
733, 1465, 1372, 1242, 1148, 1101, 1033, 918 cm ; HRMS (hexanes/EtOAc 4 : 1); [α] −56° (c 1.00, CHCl ), lit [α] −49°
3
D
D
+
+
1
(+ESI) m/z [M + Na] calcd for C H O Na 397.25606, found (c 0.282, CHCl ); H NMR (500 MHz, CDCl ) δ 7.32 (d, J = 15.8
20 38 6 3 3
3
97.25546.
3S,13R)-13-Hydroxy-3-(methoxymethoxy)tetradecanal (6).
Hz, 1 H), 6.77 (d, J = 15.8 Hz, 1 H), 5.09 (ddq, J = 2.9, 6.3, 9.1
Hz, 1 H), 4.68 (d, J = 6.8 Hz, 1 H), 4.65 (d, J = 6.8 Hz, 1 H), 4.23
(
A
solution of MOM-ether 15 (5.71 g, 15.2 mmol) in dry toluene (dd, J = 5.1, 7.2 Hz, 1 H), 3.35 (s, 3 H), 1.80 (m, 2 H), 1.59 (m, 2
1
3
(
−
3
100 mL) under an argon atmosphere was cooled down to H), 1.44–1.12 (m, 17 H) ppm; C NMR (125 MHz, CDCl
78 °C and treated with DIBAL (1 M in hexanes, 33.5 mL, 199.2, 165.1, 135.0, 132.1, 96.3, 82.0, 72.7, 56.2, 34.9, 30.6,
3.5 mmol) while stirring over a period of 15 min. Stirring was 27.82, 27.76, 27.7, 26.8, 26.6, 23.7, 22.0, 20.3 ppm; IR ν
3
) δ
max
−
1
continued for a further 75 min at −78 °C. Acetone (500 μL) was 2929, 2857, 1721, 1704, 1623, 1460, 1267, 1031, 951, 919 cm
added and the solution was stirred for 15 min. The mixture HRMS (+ESI) m/z [M + Na] calcd for C18
;
+
+
H
30
O
5
Na 349.19855,
was poured into sat. aqueous Na-K-tartrate solution (300 mL) found 349.19806.
and stirred for 1.5 h. The organic phase was separated, and
the aqueous phase was extracted with CH Cl (3 × 200 mL). dione (2). A solution of ketone 16 (50 mg, 153 μmol) in dry
The combined organic phases were washed with brine CH Cl (2 mL) was kept under argon atmosphere at −10 °C
(6S,16R,E)-6-Hydroxy-16-methyloxacyclohexadec-3-ene-2,5-
2
2
2
2
(
200 mL), dried over Na
column chromatography (petrol ether/EtOAc 2 : 1 to 1 : 1) at −10 °C, then treated with sat. aqueous NaHCO
hydroxyaldehyde 6 (4.03 g, 92%) was obtained as a colourless (40 mL), and the aqueous phase was finally extracted with
2
SO
4
and evaporated. After silica gel and treated with TFA (1 mL). The mixture was stirred for 9.5 h
3
-solution
2
0
resin. R
f
= 0.50 (hexanes/EtOAc 1 : 1); [α] +9.0° (c 1.00, CH
2
Cl
) δ 9.80 (dd, J = 1.8, 2.8 Hz, 1 over Na
H), 4.66 (dd, J = 7.0, 16.1 Hz, 2 H), 4.07 (qn, J = 6.5 Hz, 1 H), pressure. After silica gel column chromatography (hexanes/
2
(3 × 40 mL). The combined organic phases were dried
D
1
CHCl
3
); H NMR (500 MHz, CDCl
3
2
SO and the solvent was removed under reduced
4
3
1
.79 (sex, J = 5.9 Hz, 1 H), 3.35 (s, 3 H), 2.64 (ddd, J = 2.8, 7.1, EtOAc 8 : 1 to 6 : 1) alcohol 2 (38 mg, 88%) was obtained as a
1
0
f
6.3 Hz, 1 H), 2.56 (ddd, J = 1.8, 4.7, 16.3 Hz, 1 H), 1.61 (m, 1 colourless crystalline solid of mp 83–85 °C, lit 84–85 °C. R =
2
0
10
H), 1.53 (m, 1 H), 1.47–1.24 (m, 17 H), 1.20 (d, J = 6.2 Hz, 3 H) 0.38 (hexanes/EtOAc 4 : 1); [α] +35.8° (c 1.00, CHCl ), lit
ppm; C NMR (125 MHz, CDCl ) δ 201.7, 95.9, 73.3, 68.3, [α] +22.4° (c 1.0, CHCl ); H NMR (500 MHz, CDCl ) δ 7.26
3 3 3
D
D
3
1
3
20
1
5
2
5.8, 48.9, 39.5, 35.1, 29.74, 29.69, 29.68, 29.64, 29.60, 25.9, (d, J = 15.9 Hz, 1 H), 6.80 (d, J = 15.9 Hz, 1 H), 5.18 (m, 1 H),
5.3, 23.7 ppm; IR νmax 3404, 2925, 2854, 1725, 1465, 1373, 4.55 (q, J = 4.5 Hz, 1 H), 3.45 (d, J = 4.5 Hz, 1 H), 1.85 (m, 2 H),
−
1
+
1
149, 1101, 1031, 918 cm ; HRMS (+ESI) m/z [M + Na] calcd 1.73 (m, 1 H), 1.50 (m, 2 H), 1.46–1.01 (m, 15 H), 0.96 (m, 1 H)
+
13
for C16
H
32
O
4
Na 311.21928, found 311.21878.
3
ppm; C NMR (125 MHz, CDCl ) δ 201.6, 165.2, 135.0, 132.7,
(6S,16R,E)-6-(Methoxymethoxy)-16-methyloxacyclohexadec-3-
76.6, 72.8, 34.3, 31.2, 28.22, 28.17, 27.4, 27.2, 26.9, 23.5, 20.7,
en-2-one (4). A solution of Ph
3
PCCO (5, 199 mg, 659 μmol) in 19.8 ppm; IR νmax 3456, 3066, 2923, 2854, 1714, 1696, 1644,
−
1
dry toluene (55 mL) under an argon atmosphere was warmed 1459, 1353, 1286, 1190, 1057, 984 cm ; HRMS (+ESI) m/z [M +
to 55 °C and treated dropwise with a solution of hydroxyalde- Na] calcd for C H O Na 305.17233, found 305.17117.
+
+
1
6
26 4
hyde 6 (95 mg, 329 μmol) in dry toluene (10 mL) over a period
of 15 h. The resulting solution was stirred for a further 5 h col of Jacobsen aqueous NaOCl (6 wt%, 588 mL, 480 mmol)
Methyl oxirane-2-carboxylate rac-(18). According to the proto-
1
3
before the solvent was removed under reduced pressure. Silica was cooled to 0 °C and methyl acrylate (17, 31.6 mL,
4748 | Org. Biomol. Chem., 2021, 19, 4743–4751
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