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DOI: 10.1055/s-0029-1216722
Asymmetric Synthesis of (-)-Tetrahydrolipstatin from a β-Hydroxy-δ-oxo Sulfoxide
Publication History
Publication Date:
17 April 2009 (online)
Abstract
An asymmetric synthesis of (-)-tetrahydrolipstatin is described. A palladium-catalyzed regioselective oxidation of an alkene to a ketone, highly diastereoselective reduction of a β-hydroxy ketone, selective oxidation of a diol, and modular synthesis are the key features of the synthesis.
Key words
asymmetric synthesis - sulfoxide - palladium - tetrahydrolipstatin - Frater-Seebach alkylation
- Supporting Information for this article is available online:
- Supporting Information
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References and Notes
The unsaturated ester 6 was
prepared by a three-step sequence. Selective protection of 1,3-propane
diol as its
p-methoxybenzyl
ether followed by Swern oxidation and Wittig olefination afforded 6 in 40% overall yield.
Synthesis of Compound
8
A suspension of PdCl2 (352 mg, 1.98 mmol)
and CuCl (1.96 g, 19.8 mmol) in a mixture of DMF and H2O
(1:1, 20 mL) was stirred under an O2 atmosphere for 1
h. A solution of allyl alcohol 4 (7.13
g, 19.8 mmol) in DMF and H2O (1:1, 10 mL) was added to
the above, and the reaction mixture was stirred at 50 ˚C
for 4 h. The reaction mixture was extracted with Et2O
(3 × 75 mL), washed successively with
H2O (2 × 20 mL), brine (20
mL), and dried over anhyd Na2SO4. Evaporation
of the solvent in vacuo afforded the crude product which was purified
by column chromatography using 60% EtOAc-hexane
as the eluent to furnish β-hydroxy ketone 8 (5.21
g, 13.9 mmol) in 70% yield as a viscous oil. TLC: R
f
= 0.15
(70% EtOAc-hexane); [α]D +84.9
(c 0.35, CHCl3). IR (neat):
3138, 2925, 2657, 1630, 1384, 1245, 1088, 1029, 754 cm-¹. ¹H
NMR (200 MHz, CDCl3): δ = 7.67-7.59
(m, 2 H), 7.56-7.48 (m, 3 H), 7.16 (d, J = 8.8
Hz, 2 H), 6.80 (d, J = 8.8
Hz, 2 H), 4.52 (quin, J = 5.9
Hz, 1 H), 4.39 (s, 2 H), 3.78 (s, 3 H), 3.66 (t, J = 5.9
Hz, 2 H), 2.98-2.73 (m, 4 H), 2.66 (t, J = 5.9
Hz, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 208.62,
159.34, 143.63, 131.33, 129.93, 129.43, 129.35, 123.99, 113.87,
72.91, 64.73, 61.99, 55.28, 49.02, 43.67. ESI-MS: 399 [M + Na]+.
ESI-HRMS: m/z [M + Na]+ calcd
for C20H24O5NaS: 399.1242; found:
399.1240.
Synthesis of Compound 9
To
a solution of β-hydroxy ketone 8 (5.21
g, 13.9 mmol) in THF (110 mL) cooled at -78 ˚C
was added diethylmethoxy-borane (1 M in THF, 15.4 mL, 15.4 mmol)
followed by MeOH (28 mL), and stirred for 30 min. Then solid NaBH4 (577
mg, 15.3 mmol) was added in three portions and the mixture stirred
for 2 h at the same temperature. The reaction was quenched using
a mixture of pH 7 phosphate buffer (20 mL), MeOH (30 mL), and 30% (w/v)
H2O2 soln (10 mL). This mixture was allowed
to warm to r.t. and stirred at r.t. for further 18 h. The organic
solvent was evaporated in vacuo, and the aqueous layer was extracted
with Et2O (3 × 75 mL). The
combined organic layers were washed with brine (20 mL) and dried
over anhyd Na2SO4. Evaporation of the solvent
in vacuo yielded the crude product, which was purified by column
chromatography using 65% EtOAc-hexane as the eluent
to afford the syn 1,3-diol 9 (3.82 g, 10.1 mmol) in 73% yield
as a viscous oil. TLC: R
f
= 0.2
(70% EtOAc-hexane); [α]D +56
(c 2.25, CHCl3). IR (neat):
3386, 2923, 2856, 2362, 1611, 1512, 1441, 1303, 1246, 1175, 1088,
1030, 820, 753, 691, 503 cm-¹. ¹H
NMR (300 MHz, CDCl3): δ = 7.67-7.62
(m, 2 H), 7.55-7.46 (m, 3 H), 7.18 (d, J = 8.3
Hz, 2 H), 6.82 (d, J = 8.3
Hz, 2 H), 4.41 (s, 2 H), 4.36-4.24 (m, 1 H), 3.78 (s, 3
H), 3.69-3.53 (m, 3 H), 3.03 (dd, J = 7.6,
12.8 Hz, 1 H), 2.80 (dd, J = 4.5,
12.8 Hz, 1 H), 1.86-1.62 (m, 4 H). ¹³C
NMR (75 MHz, CDCl3): δ = 159.37, 143.86,
131.21, 129.84, 129.36, 124.08, 113.93, 77.01, 73.05, 71.54, 68.43,
63.42, 55.28, 42.71, 29.68. ESI-MS: 401 [M + Na]+.
ESI-HRMS: m/z [M + Na]+ calcd
for C20H26O5NaS: 401.1398; found:
401.1405.
Synthesis of Compound 12
To
a suspension of NaH (60% in Nujol, 310 mg, 7.7 mmol) in
anhyd THF (10 mL), cooled at 0 ˚C, was added a
solution of diol 11 (810 mg, 3.1 mmol)
in THF (20 mL) dropwise. The mixture was gradually allowed to warm
to r.t. and further stirred for 1 h at the same temperature. It
was then recooled at 0 ˚C and N-Ts-Imd
(686 mg, 3.1 mmol) was added in three equal potions over a period
of 20 min. The mixture was warmed to r.t. and stirred for 40 min,
then CuCN (55 mg, 0.61 mmol) was added. After stirring for an additional
5 min, the mixture was cooled at -10 ˚C, and a freshly
prepared solution of decylmagnesium bromide (0.7 M in Et2O,
13.3 mL, 9.31 mmol) was added via syringe. The reaction mixture
was kept at the same temperature for 2 h and then allowed to warm
to 0 ˚C gradually over a period of 1 h. The reaction was
quenched by the addition of aq sat. NH4Cl solution (10
mL) and diluted with Et2O (65 mL). The separated organic
phase was washed with H2O (2 × 25
mL) and brine (25 mL). The aqueous layers were re-extracted with
Et2O (2 × 25 mL), and the
combined organic layers were dried over anhyd Na2SO4.
Evaporation of the solvent in vacuo furnished the crude residue
which was purified by column chromatography using 10% EtOAc-hexane
as the eluent to afford triol 12 (846 mg,
2.1 mmol) in 70% yield as a viscous oil. TLC: R
f
= 0.5
(20% EtOAc-hexane); [α]D
-14.9
(c 1.1, CHCl3). IR (neat):
3447, 2922, 2853, 1634, 1459, 558 cm-¹. ¹H
NMR (300 MHz, CDCl3): δ = 7.31 (d, J = 9.1 Hz,
2 H), 6.82 (d, J = 9.1
Hz, 2 H), 5.45 (s, 1 H), 4.22 (dd, J = 4.5,
12.1 Hz, 1 H), 4.13-4.02 (m, 1 H), 3.92 (dt, J = 2.3, 12.1
Hz, 1 H), 3.86-3.80 (m, 1 H), 3.78 (s, 3 H), 1.92-1.23
(m, 24 H), 0.88 (distorted t, J = 6.8
Hz, 3 H).
¹³C NMR (100 MHz,
CDCl3): δ = 159.83, 130.67, 127.15, 113.57,
101.07, 78.10, 71.36, 66.98, 55.32, 42.77, 37.66, 31.56, 29.72,
29.69, 29.42, 25.51, 22.76, 14.22. ESI-MS: 393 [M + H]+.
ESI-HRMS: m/z [M + Na]+ calcd
for C24H40O4Na: 415.2824; found:
415.2804.