4118
T. MuK^n'^M^
preparative tic to give the corresponding alcohol. Further it was
purified for the measurement of specific rotation by bulb-to-bulb
distillation.
Asymmetric syntheses of ( - )-frontalin(22S), ( + )-frontalin (22R)
Keto aminal 19 was prepared from 15 and 4 - methyl - 4 -
pcntenylmagnesium bromide in 63% yield based on la by
a
similar method described above with the exception that the
Grignard reaction was carried out at - 100~. Keto aminal 19 was
treated with MeMgBr at -78° and the resulting hydroxy aminal
was hydrolyzed to yield 28S, which was further reduced with
NaBI-~ at 0° without purification. Diol (21S) was obtained in 69%
yield from 19 after purification by silica gel column chromato-
graphy ( [ a ] ~ - 2.0 (c 0.98, CH2CI2), Ozonolysis of 21S at -700
in CH2CI2 followed by a reductive work up with Me2S at room
temp afforded 22S in 91% yield after purification by alumina
column chromatography, [a]~ -45.50 (c 1.75, ether) whose
optical purity was 84% - 88%.
Asymmetric addition of alkyllithium to an aldehyde in
mixture of dimethoxymethane and methyl ether
a I:1
Immediately after evaporation of
a soln of alkyilithium
(6.75mmol5 in vacuo at &, dimethoxymethane (10ml) and
2
(4.05mmol) in 2.5ml dimethoxymethane were added suc-
cessively at -78° under an argon atmosphere. The mixture was
stirred for 30rain, and 13 ml methyl ether was introduced. After
cooling the mixture to - 123°, a dimethoxymethane (0.5 ml) soln
of an aldehyde (I mmol) was added. After stirring for I hr a t -
123", the reaction was quenched with 3N HCI, and the product
was extracted with ether. The ethereal extract was dried over
Na2SO4 and concentrated. The alcohol was separated by silica gel
tic using CH2C12 as a developing solvent and the isolated product
was further purified by bulb-to-bulb distillation.
(+)
- Frontalin (22R) was also obtained according to the
present procedure only by changing the order of the introduction
of substituents originated from the Grignard reagent. (R)-Diol
(21R) was obtained by a similar treatment in 71% yield from 16,
[a]~s +2.40 (c 1.12, CH2CI2), which was converted into (+) -
frontalin (22R), [a]~ + 54.30 (c 3.39, ether), whose optical purity
was 100%.
Asymmetric addition of dialkylmagnesium to an aldehyde in
toluene
To an ether (7ml) soln of
(4retool), followed by addition of an ether soln of dia]kyl-
magnesium (4mmol) at &. The solvent was removed under
2 (4mmol) was added n-BuLl
Asymmetric synthesis of ( - )- malyngolide (30).
Keto aminal (23) was prepared by the reaction of 15 with
4-pentenylmagnesium bromide in the presence of MgCI2 at
-
reduced pressure. After the mixture was cooled t o - I I 0°,
a
100°. The animal 23 was treated with nonylmagnesium bromide
at -100~ and the resulting hydroxy aminal was hydrolyzed to
yield 24, which was immediately reduced with NaBH4 at room
temp. The diol (25) was obtained in 52% overall yield from 15
after purification by silica gel column chromatography. The pro-
tection of the primary OH group of 25 was accomplished in 98%
yield by treatment with t-butyldimethylsilyl chloride, triethyl-
toluene (2 ml) soln of an aldehyde was added dropwise and the
stirring was continued for I hr a t - ll&. The reaction was quen-
ched with 3N HCI. Similar workup as described above gave the
pure alcohol.
Asymmetric addition o/lithium trimethylsilylacetylide
To a soln of 2 (4 mmol) in dimethyl ether (20 ml) was added a
soln of (Mes)SiL~--CH (2.7 ram,l) in 2 ml dimethoxymethane, fol-
lowed by the addition of n-BuLl (6.7 retool, 4.3 m[ in hexane)
at - 35°. After stirring for 30 min at the same temp, the resulting
white suspension was cooled to- 123°. A soln of an aldehyde
(1 retool) in 2ml dimethoxymethane was added dropwise and
stirring was continued for an additional l hr. The mixture was
treated with 2N HCI, and was extracted with ether. The organic
layer was dried over Na2SO4 and concentrated. After the removal
of the solvent, the corresponding alcohol was purified by tic
(silica gel). The opticaJ purity of the resulting alcohol was
determined by NMR measurement of its MTPA derivative
(Mosher's method) utilizing benzene-d6 as a solvent.
amine and
a catalytic amount of 4 - dimethylaminopyridine.
Ozonolysis of the resulting 26 at -78° in MeOH followed by
reductive work up with MesS at room temp afforded 27 in 69%
yield after purification by silica gel column chromatography. The
lactol (27) was oxidized to 28 with pyridinium dichromate in
N,N-dimethylformamide at room temp in almost quantitative
yield. The lactone 28 was treated with lithium diisopropyl-amide
at -780 in the presence of HMPA, and alkylated with Mel to
afford a diastereomeric mixture of 29 in 74% yield. These methyl
lactones were desilylated by treatment with tetrabutylammonium
fluoride to yield
a diastereomeric mixture of 30 and its C-2
epimer (30') in 58% and 29% yield respectively. The separated
C-2 epimer (30') was easily epimerized to approx. 1:1 mixture of
30 and 30' by treatment with KOBut in DMSO.
Keto aminal;
2
-
acyl - 3 - phenyl - 1,3 - diazabicy-
clo[3,3,0]octane (165
Asymmetric syntheses of 3-alkylsuccinaldehydic acid methyl
esters (32)
Methyl hydroxymethoxyacetate (15.8 retool) was treated with
la (15.0 retool) with removal of water azeotropically in refluxing
benzene (25 ml) for 30 rain. The solvent was evaporated under
reduced pressure and the resulting I$ was used without further
purification. To a soln of !$(15 retool) in THF (75 ml) was added
anhyd MgC12 (16.5 retool) and refluxed for 10 rain. The soln was
cooled to - 70°, and 1.36 equiv of Grignard reagent in ether was
added. After I hr, sat NH4CIaq was added to the mixture. The
mixture was extracted with ether and the ethereal extract was
washed with brine. The crude product was purified by alumina
column chromatography to give 16.
The amine 31 was prepared by the reaction of la (20 mmol)
and fumaraldehydic acid methyl ester (22 retool) in THF (200 ml)
in the presence of molecular sieves (10g). After the filtration and
the removal of solvent, the resulting solid was recrystallized
from cyclohexane to give 31 (80% m.p. 85-86° [a]~ -59. 0° (c
1.03, EtOH). An ethereal soln of Grignard reagent (2 retool) was
added to the ethereal mixture (15 ml) of 31 (1 retool) and Cul
(0.05 mmul) at -780 under an argon atmosphere. The mixtme
was stiffed at -78° for 4 hr, then quenched with sat NH4Claq.
The aqueous layer was neutralized with NaHCO3aq, followed by
extraction with ether and the combined ethereal soln was
hydrolyzed with 10ml 2% HC1 at room temp for 2hr. The
ethereal layer was dried over Na2SO, and the solvent was
evaporated. The resulting oily substance was purified by silica gel
column chromatography to give the corresponding 32. It was
further purified by bulb-to-bulb distillation. Enantiomeric exces-
ses were estimated by 60MHz tH NMR by using tris[3-
(heptafluoropropylhydroxymethy[ene) - d - camphorato] - euro-
pium (Ill) as shift reagent.
Asymmetric syntheses of a-hydroxyaldehydes (185
To an ethereal soln (5ml) of 16 (I.I mmol) was added
a
Grignard reagent (2.2 ram,l) in ether at -70°. After I hr, sat
NH~Claq was added to the mixture. The ethereal layer was
separated and washed with IN NaOH. The ethereal layer was
treated with 2% HCI at 0° for 12br. The ethereal layer was
separated and washed with brine. The solvent was evaporated
under reduced pressure to yield oily substance. The crude
product was purified by silica gel column chromatography and
the corresponding a-hydroxyaldehyde (18) was isolated, which
was thoroughly purified by bulb-to-bulb distillation.
Asymmetric synthesis o/3 - alkyl - 2 - oxaindanes (lactol) (34)
and (S) - 3 - butylphtalide
The aminal 33 was prepared easily by mixing la (15 ram*l) and
o-bromohenzaldehyde (15 ram,l) in refluxing benzene and was
recrystallized from cyclohexane: m.p. 169-170.5° [c~]~+250 (c
In the case of Igb, lg¢, Ire, those were isolated as benzyl ether
by the benzylation (Nail, PhCH2Br in DMSO) of the inter-
mediate 17 followed by the hydrolysis.
Mukaiyama, Teruaki
