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A. M. Teitelbaum et al.
Paper
Synthesis
trans-2-Methyl-3-(5′-formyl-3′-methylpent-2′-enyl)-1,4-naphtho-
quinone (7)
1H NMR (500 MHz, CDCl3): δ = 1.51 (s, 6 H), 1.53–1.57 (m, 12 H), 1.67
(s, 1 H), 1.78 (s, 1 H), 1.88 (d, J = 9.3 Hz, 2 H), 2.45 (dd, J = 14.7, 6.9 Hz,
2 H), 2.82 (dd, J = 14.9, 7.1 Hz, 2 H), 3.12 (br s, 2 H), 3.20 (br s, 2 H),
4.89 (t, J = 6.9 Hz, 2 H), 6.00–6.05 (m, 4 H), 7.61–7.67 (m, 4 H), 7.83–
7.90 (m, 2 H), 7.91–7.96 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 17.8, 23.5, 25.7, 36.2, 43.6, 53.8, 55.3,
57.2, 68.9, 119.9, 126.1, 126.8, 133.4, 133.8, 133.9, 134.9, 136.8, 137.4,
138.2, 201.4, 202.2.
A solution of periodic acid (38.7 mg, 0.170 mmol) in H2O (2.0 mL) was
added dropwise to a solution of epoxide 6 (37.0 mg, 0.114 mmol) in
THF (2.0 mL) at r.t. After stirring for 60 min, the reaction mixture was
diluted with Et2O (20 mL) and the organic layer was washed succes-
sively with aq 5% NaHCO3 (5 mL), H2O (5 mL), and brine (5 mL). The
organic layer was collected, dried (MgSO4), evaporated, and the prod-
uct was purified by flash column chromatography to yield aldehyde 7
as a yellow oil; yield: 20.7 mg (65%).
HRMS (ESI): m/z calcd for C21H23O2 [M + H]+: 307.1693; found:
307.1698 (error 1.7 ppm).
IR (neat): 2935, 2893, 1729, 1662, 1598, 1462, 1298, 718 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.82 (s, 3 H), 2.18 (s, 3 H), 2.29–2.37
(m, 2 H), 2.49–2.55 (m, 2 H), 3.37 (d, J = 6.8 Hz, 2 H), 5.07 (t, J = 6.6, 1
Hz), 7.70 (m, 2 H), 8.05–8.13 (m, 2 H), 9.73 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 12.7, 16.4, 26.0, 31.7, 42.0, 120.3,
126.2, 126.3, 132.1 (ovlp 2 C), 133.3 (ovlp 2 C), 135.5, 143.5, 145.6,
184.4, 185.3, 202.0.
2-Methyl-3-(3′-methylbut-2′-enyl)-1,4-naphthoquinone (9)
Intermediate 8 (583 mg, 1.90 mmol) and dodecyltrimethylammoni-
um bromide (34 mg) were dissolved in AcOH (5 mL) and stirred at
90 °C for 1 h and then cooled to r.t. Et2O (30 mL) was added followed
by successive washes of the organic phase with distilled H2O (10 mL)
and brine (10 mL). The organic layer was collected, dried (MgSO4),
concentrated, and purified by flash column chromatography (5%
EtOAc–hexanes) to afford 9 as a yellow oil; yield: 357 mg (78%).
HRMS (ESI): m/z calcd for C18H19O3 [M + H]+: 283.1329; found:
283.1332 (error 1.3 ppm).
IR (neat): 2935, 1663, 1598, 1460, 1379, 1332, 1298, 715 cm–1
.
trans-2-Methyl-3-(5′-carboxy-3′-methylpent-2′-enyl)-1,4-naph-
thoquinone (1)
1H NMR (500 MHz, CDCl3): δ = 1.69 (s, 3 H), 1.79 (s, 3 H), 2.19 (s, 3 H),
3.35 (d, J = 6.9 Hz, 2 H), 5.01 (t, J = 6.4 Hz, 1 H), 7.63–7.70 (m, 2 H),
8.01–8.10 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 12.6, 17.9, 25.7, 26.1, 119.1, 126.1,
126.2, 132.0, 133.2, 133.2 (ovlp 2 C), 133.9, 143.2, 146.0, 184.4, 185.3.
To a solution of aldehyde 7 (19.7 mg, 0.070 mmol) in DMF (2 mL) was
added KHSO5 (94.4 mg, 0.307 mmol) and the reaction mixture was
stirred at r.t. for 2.5 h. Et2O (20 mL) was added to the mixture and the
Et2O layer was subsequently washed with H2O (5 mL) and brine (5
mL). The organic layer was dried (MgSO4), evaporated, and the prod-
uct was purified by flash column chromatography (40% EtOAc–hex-
anes) to yield vitamin K acid 1 (1) as a yellow solid; yield: 14.3 mg
(70%); mp 118–120 °C
HRMS (ESI): m/z calcd for C16H17O2 [M + H]+: 241.1223; found:
241.1227 (error 1.6 ppm).
trans-2-Methyl-3-(4′-hydroxy-3′-methylbut-2′-enyl)-1,4-naphtho-
quinone (10)
IR (KBr): 2935, 2899, 1702, 1661, 1645, 1437, 1300, 1226, 866, 787,
SeO2 (2.73 mg, 0.025 mmol) and salicylic acid (3.41 mg, 0.025 mmol)
were suspended in CH2Cl2 (1.25 mL) followed by the addition of aq
70% tert-butyl hydroperoxide (65.1 mg, 0.723 mmol). The mixture
was stirred for 10 min at r.t. and then cooled to 0 °C. A solution of
compound 9 (59.2 mg, 0.246 mmol) in CH2Cl2 (1.25 mL) was added
dropwise and the mixture was allowed to warm to r.t. and stirred for
48 h. After dilution with Et2O (20 mL), the organic layer was washed
with aq 5% NaHCO3 (5 mL), sat. aq CuSO4 (5 mL), sat. aq Na2SO3 (5 mL),
H2O (5 mL), and brine (5 mL). The organic layer was collected, dried
(MgSO4), and the solvent was evaporated. The crude product was pu-
rified by flash column chromatography (10–50% EtOAc–hexanes) to
afford allylic alcohol 10 as a yellow oil; yield: 36.4 mg (57%).
717 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.82 (s, 3 H, CH3 at C3′), 2.18 (s, 3 H,
CH3 at C2), 2.28–2.36 (m, 2 H, CH2 at C4′), 2.38–2.48 (m, 2 H, CH2 at
C5′), 3.38 (d, J = 6.9 Hz, 2 H, CH2 at C1′), 5.09 (t, J = 6.4 Hz, 1 H, CH at
C2′), 7.65–7.77 (m, 2 H, CH at C6, CH at C7), 8.03–8.15 (m, 2 H, CH at
C5, CH at C8).
13C NMR (125 MHz, CDCl3): δ = 12.6 (CH3 at C2), 16.2 (CH3 at C3′), 25.9
(C1′), 32.5 (C5′), 34.2 (C4′), 120.3 (C2′), 126.2 (C5), 126.3 (C8), 132.1
(ovlp C9, C10), 133.3 (C6), 133.4 (C7), 135.4 (C3′), 143.6 (C2), 145.6
(C3), 178.5 (C6′), 184.4 (C4), 185.3 (C1).
HRMS (ESI): m/z calcd for C18H19O4 [M + H]+: 299.1278; found:
299.1284 (error 2.2 ppm).
IR (neat): 2929, 2858, 1662, 1598, 1298, 718 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.86 (s, 3 H), 2.21 (s, 3 H), 3.43 (d, J =
7.3 Hz, 2 H), 4.02 (s, 2 H), 5.34 (t, J = 6.6 Hz, 1 H), 7.67–7.73 (m, 2 H),
8.06–8.11 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 12.7, 13.9, 25.7, 68.4, 120.4, 126.2,
126.3, 132.1 (ovlp 2 C), 133.4 (ovlp 2 C), 137.0, 143.6, 145.4, 184.4,
185.3.
Protected Menadione Dimethylallyl Adduct 8
Protected menadione adduct 3 (102.4 mg, 0.430 mmol) was dissolved
in a 1.0 M solution of KOt-Bu in THF (2.2 mL, 2.24 mmol) under N2 at
0 °C. The blood-red solution stirred for 30 min and dimethylallyl
chloride (89.9 mmol, 1.72 mmol) was added dropwise and the stirred
reaction mixture was warmed to r.t. After 3 h, the pH of the solution
was adjusted to 2–3 by the addition of aq 1 M HCl, and Et2O (20 mL)
was added. The organic layer was washed with H2O (5 mL) and brine
(5 mL), dried (MgSO4), and concentrated. The crude product was puri-
fied by flash column chromatography (10% EtOAc–hexanes) to afford
compound 8 as a dark yellow oil; yield: 108 mg (82%); 1:1 pair of dias-
tereomers.
HRMS (ESI): m/z calcd for C16H17O3 [M + H]+: 257.1172; found:
257.1176 (error 1.5 ppm).
2-Methyl-3-(4′-hydroxy-3′-methylbutyl)-1,4-naphthoquinone (11)
Cs2CO3 (49.2 mg, 0.152 mmol) and ruthenium catalyst [RuCl(μ-Cl)(μ6-
p-cymene)]2 (46.3 mg, 0.076 mmol) was added to a solution of allylic
alcohol 10 (77.8 mg, 0.304 mmol) in i-PrOH (3 mL). The mixture was
refluxed overnight at 80 °C and subsequently diluted with Et2O (20
mL), and the organic layer was washed with H2O (5 mL) and brine (5
IR (neat): 2989, 2935, 2365, 1662, 1596, 1297, 715, 668 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 944–948