Lipase-mediated synthesis of enantiopure N-carbobenzoxy-3-hydroxy- 1,2,3,4-tetrahydro- and N-carbobenzoxy-3-hydroxy-1,2,3,6-tetrahydropyridines from 3-hydroxypyridine

Article abstract of DOI:10.1055/s-2000-6363

Two isomeric chiral hydroxytetrahydropyridines, having high potential utility for the construction of a variety of chiral amine derivatives, have been prepared in both enantiomeric forms by employing lipase-mediated resolution starting from 3-hydroxypyridine. Thus, on exposure to sodium borohydride in the presence of carbobenzoxy chloride, 3-hydroxypyridine has been found to furnish racemic N-carbobenzoxy-3-hydroxy-1,2,3,4- tetrahydropyridine, which is resolved under trans-esterification conditions in the presence of lipase PS to give both enantiomeric products in enantiopure forms. Isomerization of the chiral 1,2,3,4-tetrahydro-product into the chiral 1,2,3,6-tetrahydro-derivative has been accomplished without loss of the original chiral integrity. The racemic 1,2,3,6-tetrahydro- derivative has also been resolved under the same lipase-mediated trans- esterification conditions.

Full text of DOI:10.1055/s-2000-6363

PAPER
521
Lipase-Mediated Synthesis of Enantiopure N-Carbobenzoxy-3-hydroxy-
1,2,3,4-tetrahydro- and N-Carbobenzoxy-3-hydroxy-1,2,3,6-
tetrahydropyridines from 3-Hydroxypyridine
Hideki Sakagami, Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81(22)2176845; E-mail: konol@mail.cc.tohoku.ac.jp
Received 17 November 1999; revised 5 January 2000
Abstract: Two isomeric chiral hydroxytetrahydropyridines, having
high potential utility for the construction of a variety of chiral amine
derivatives, have been prepared in both enantiomeric forms by em-
ploying lipase-mediated resolution starting from 3-hydroxypyri-
dine. Thus, on exposure to sodium borohydride in the presence of
carbobenzoxy chloride, 3-hydroxypyridine has been found to fur-
nish racemic N-carbobenzoxy-3-hydroxy-1,2,3,4-tetrahydropyri-
dine, which is resolved under trans-esterification conditions in the
presence of lipase PS to give both enantiomeric products in enan-
tiopure forms. Isomerization of the chiral 1,2,3,4-tetrahydro-prod-
uct into the chiral 1,2,3,6-tetrahydro-derivative has been
accomplished without loss of the original chiral integrity. The race-
mic 1,2,3,6-tetrahydro-derivative has also been resolved under the
same lipase-mediated trans-esterification conditions.
Scheme 1
Key words: Lipase-mediated kinetic resolution, trans-esterifica-
tion, chiral building block, tetrahydropyridinol, regioselective re-
duction
diate 7 which, in turn, was isomerized to the ketone 8 and
reduced to give rise to the final 1,2,3,4-tetrahydro-product
(±)-9 (Scheme 2).
Allylic alcohols, such as 2 and 4, which are located on the
piperidine ring system, have high potential as versatile in-
termediates for the construction of a variety of alkaloids.
Their synthesis, however, is not an easy task as it took 10
and 8 steps, respectively, to obtain (±)-21 and (±)-42 from
the readily available starting materials (Scheme 1). There-
fore, development of an efficient procedure for the prepa-
ration of these compounds in enantiopure forms would
have undoubtedly considerable synthetic merit. In this pa-
per, we wish to report the synthesis of N-carbobenzoxy-3-
hydroxy-1,2,3,6-tetrahydropyridine 9, the structural iso-
mer of 2, in a single step3a from 3-hydroxypyridine 5, its
kinetic resolution4 using lipase PS (Pseudomonas sp.
Amano) and its transformation into 2 in enantiopure
forms.3b
Since it has been reported5 that reduction of pyridine with
sodium borohydride in the presence of methyl chlorofor-
mate afforded N-carbomethoxy-1,2-dihydropyridine, we
treated 3-hydroxypyridine 5 with sodium borohydride and
carbobenzoxy chloride in the presence of sodium hydro-
gen carbonate in expectation of generating the N,O-dicar-
bobenzoxylated 1,2-dihydropyridine. Contrary to our
expectation, the reaction proceeded in an unprecedented
way to furnish N-carbobenzoxy-3-hydroxy-1,2,3,4-tet-
rahydropyridine (±)-9 in 70% yield. The reaction was pre-
sumed to occur by initial formation of the
carbobenzoxypyridinium boronate complex 6, allowing
regioselective reduction to give the 1,2-dihydro-interme-
Having discovered the unprecedented reductive carbam-
oylation of 3-hydroxypyridine 5, we examined lipase-me-
diated resolution of the resulting cyclic homoallylic
alcohol (±)-9. Thus, when (±)-9 was stirred with vinyl ac-
etate in dichloromethane in the presence of lipase PS at
30 °C, a clear-cut kinetic resolution occurred to give the
(R)-acetate 10 in 47% yield leaving the (S)-alcohol 9 in
48% recovery yield, both with >99% ee. The latter was
converted into the former in 49% yield without loss of the
original chiral integrity by the Mitsunobu reaction6 with
acetic acid. The acetate (R)-10 gave the alcohol (R)-9 on
alkaline methanolysis, while the alcohol (S)-9 gave the ac-
etate (S)-10 under standard acetylation conditions
(Scheme 3). The absolute configuration of the resolution
products was determined3b by the conversion of the reso-
lution product into (R)-4-amino-3-hydroxybutanoic
acid7,8 (GABOB), a hypotensive and antiseptic drug hav-
ing the established structure.
Isomerization of the resolved alcohol 9 into the isomeric
alcohol N-carbobenzoxy-3-hydroxy-1,2,3,6-tetrahydro-
pyridine 2 was next examined. Since it was presumed that
a 2,3-dihydropyridinium salt such as 13 may be an essen-
tial intermediate to give 2 by regiospecific 1,2-reduction,
9 was first treated with N-bromosuccinimide (NBS) to ob-
tain the bromoacetal 11 to serve as the precursor of 13.
Upon treatment in methanol, (R)-9 furnished the bro-
moacetal 11 regioselectively in 90% yield as a mixture of
Synthesis 2000, No. 4, 521–524 ISSN 0039-7881 © Thieme Stuttgart · New York

522
H. Sakagami, K. Ogasawara
PAPER
Scheme 2
In conclusion, the reduction of 3-hydroxypyridine with
sodium borohydride in the presence of carbobenzoxy
chloride was found to proceed in an unprecedented way to
give rise to N-carbobenzoxy-3-hydroxy-1,2,3,4-tetrahy-
dropyridine (±)-9. This was resolved under lipase-mediat-
ed trans-esterification conditions to give the (R)-acetate
(R)-10 leaving the (S)-alcohol (S)-9, both with >99% ee.
The chiral alcohol (R)-9 was transformed into the isomer-
ic N-carbobenzoxy-3-hydroxy-1,2,3,4-tetrahydropyridine
(S)-2, without loss of the original chiral integrity, which
was also obtained from the racemic substrate (±)-2 in
enantiomerically pure forms employing the same lipase-
mediated trans-esterification conditions.
Scheme 3
Mps are uncorrected. IR spectra were recorded on a JASCO-IR-700
spectrometer. H NMR spectra were recorded on a Gemini 2000
(300 MHz) spectrometer. Enantiomeric excess was determined on a
Gilson Model-307 instrument equipped with a chiral column. Opti-
cal rotations were measured with a JASCO-DIP-370 digital pola-
rimeter.
epimers. Without separation, the mixture was refluxed
with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in tolu-
ene to give the allyl acetal 12 which was treated with bo-
ron trifluoride, followed by sodium cyanoborohydride in
tetrahydrofuran (THF) to accomplish concurrent forma-
tion of the iminium salt 13 and its specific 1,2-reduction
to 2.9 Gratifyingly, the desired allyl alcohol (S)-2 was ob-
tained in 61% overall yield from the bromoacetal 11 under
these conditions without loss of the original chiral integri-
ty. The alcohol (S)-2 thus obtained gave the acetate (S)-14
under standard acetylation conditions (Scheme 4).
The racemic alcohol1 (±)-2 was also resolved under the
same lipase-mediated conditions as mentioned above.3c
Thus, treatment of (±)-2 with vinyl acetate in dichlo-
romethane in the presence of lipase PS afforded the ace-
tate (S)-14 in 47% yield leaving the alcohol (R)-2 in 48%
recovery yield, both with >99% ee. The former gave the
alcohol (S)-2 on alkaline methanolysis. On the other hand,
the same alcohol (S)-2 was also obtained from the enanti-
omeric alcohol (R)-2 on Mitsunobu inversion using 4-ni-
trobenzoic acid10 followed by methanolysis of the
1
(±)-N-Carbobenzoxy-3-hydroxy-1,2,3,4-tetrahydropyridine
(±)-9
To a stirred suspension of 3-hydroxypyridine 5 (6.0 g, 61.8 mmol),
NaBH4 (5.1 g, 136.0 mmol) and NaHCO3 (3.9 g, 46.4 mmol) in
EtOH (250 mL) was added carbobenzoxy chloride (13.2 mL,
92.7 mmol), in portions, at -78 °C. The mixture was then stirred for
1.5 h at the same temperature. The reaction was quenched by addi-
tion of K2CO3 (1.0 g) at the same temperature. The mixture, after
filtration through a Celite pad, was evaporated under reduced pres-
sure, and the residue was extracted with EtOAc (2 ¥ 300 mL). The
extract was washed with brine (70 mL), dried (MgSO4), evaporated
under reduced pressure, and chromatographed (SiO2, 500 g, EtOAc/
hexane, 1:2) to give the homoallyl alcohol (±)-9 (10.2 g, 70%) as a
colorless oil.
IR (film): n = 3400, 1704 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.34 (s, 5H), 6.96-6.81 (m, 1H),
5.20 (s, 2H), 4.88-4.72 (m, 1H), 4.26-4.07 (m, 1H), 3.79-3.52 (m,
inverted benzoate product, but its enantiomeric purity was 2H), 2.49-2.31 (m, 1H), 2.20-1.88 (m, 2H).
MS: m/z = 233 (M+), 91 (100%).
HRMS: m/z calcd for C13H15NO3 (M+) 233.1052. Found: 233.1045.
found to be somewhat decreased under these conditions
(~89% ee) (Scheme 5).
Scheme 4
Synthesis 2000, No. 4, 521–524 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Lipase-Mediated Synthesis of Enantiopure N-Carbobenzoxy-3-hydroxy-1,2,3,4-tetrahydro-
523
Conversion of the Alcohol (S)-9 into the Inverted Acetate (R)-10
To a stirred solution of (S)-9 (99% ee) (228 mg, 0.98 mmol) in THF
(5 mL) were added Ph3P (334 mg, 1.27 mmol), diisopropyl azodi-
carboxylate (DIAD) (0.25 mL, 1.27 mmol) and HOAc (0.07 mL,
1.27 mmol) at 0 °C. After stirring at r.t. for 3 h, the mixture was
evaporated under reduced pressure, and the residue was chromato-
graphed (SiO2, 100 g, EtOAc/hexane, 1:4) to give the acetate (R)-10
(132 mg, 49%), [a]D29 +13.8 (c 0.93, CHCl3). Spectral data were
identical to those of (S)-10. Enantiomeric excess was determined as
99% ee by HPLC using a column with a chiral stationary phase
(CHIRALCEL OD, 2% PriOH/hexane).
Scheme 5
N-Benzoxy-3-bromo-5-hydroxy-2-methoxypiperidine 11
To a stirred solution of alcohol (R)-9 (7.7 g, 33.0 mmol) in MeOH
(170 mL) was added N-bromosuccinimide (NBS) (6.5 g, 36.4
mmol) at 0 °C and the mixture was stirred at the same temperature
for 1 h. The mixture was washed successively with 5% NaHCO3 (50
mL) and 10% Na2S2O3 (50 mL), dried (MgSO4), and chromato-
graphed (SiO2, 70 g, EtOAc/hexane, 1:2) to give the bromo-ether 11
(10.2 g, 90%) as a colorless oil, as a diastereomeric mixture.
IR (film): n = 3456, 1684 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.35 (s, 5H), 5.87-4.96 (m, 4H),
4.54-3.82 (m, 3H), 3.46-3.05 (m, 3H), 2.95-1.88 (m, 3H).
Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C,
66.73; H, 6.52; N, 5.77.
Resolution of Racemic N-Carbobenzoxy-3-hydroxy-1,2,3,4-tet-
rahydropyridine (±)-9
A stirred mixture of the racemic alcohol (±)-9 (6.25 g, 26.8 mmol),
vinyl acetate (7.4 mL, 80.4 mmol) in CH2Cl2 (179 mL) was sus-
pended with immobilized lipase, Lipase PS (Pseudomonas sp.,
Amano) (6.25 g), and the suspension was stirred at 30 °C for 60 h.
The mixture, after filtration through a Celite pad, was evaporated
under reduced pressure and chromatographed (SiO2, 150 g, EtOAc/
hexane, 1:2~4) to give the (R)-acetate 10 (3.49 g, 47%), [a]D29 +13.0
MS: m/z = 343 (M+), 312 (M+-31), 91 (100%).
HRMS: m/z calcd for C14H18BrNO4 (M+) 343.0419. Found:
(c 1.04, CHCl3), as
a colorless oil and the (S)-alcohol 9
343.0417.
(3.01 g, 48%), [a]D27 +7.12 (c 0.96, CHCl3), as a colorless oil. The
enantiomeric excess of (R)-10 was determined as 99% ee by HPLC
using a column with a chiral stationary phase (CHIRALCEL OD,
elution with 2% PriOH/hexane: tR = 38.8 min for (R)-10 and 32.8
min for (S)-10 at 0.5 mL/min). The enantiomeric excess of (S)-9
was determined as >99% ee by HPLC as for (R)-10 after transfor-
mation into the acetate (S)-10.
Anal. Calcd for C14H18BrNO4: C, 48.85; H, 5.27; N, 4.07; Br, 23.31.
Found: C, 49.00; H, 5.33; N, 3.97; Br, 23.23.
(S)-N-Carbobenzoxy-3-hydroxy-1,2,3,6-tetrahydropyridine
(S)-2
A mixture of the bromo-ether 11 (2.9 g, 8.43 mmol) and 1,8-diaz-
abicyclo[5.4.0]undec-7-ene (DBU) (2.5 mL, 16.9 mmol) in toluene
(17 mL) was refluxed for 12 h. After cooling, the mixture was dilut-
ed with Et2O (200 mL) and then washed successively with H2O
(50 mL) and brine (50 mL), dried (MgSO4) and evaporated under
reduced pressure.
(R)-10: IR (film): n = 1735, 1711 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.36 (s, 5H), 6.98-6.78 (m, 1H),
5.23-5.07 (m, 3H), 4.95-4.69 (m, 1H), 3.87-3.74 (m, 1H), 3.67-
3.57 (m, 1H), 2.47-2.32 (m, 1H), 2.20-2.08 (m, 1H), 2.08-1.99
(m, 3H).
The residue containing the allyl alcohol 12 was then dissolved in
THF (52 mL) and the solution was treated with BF3∑OEt2 (1.9 mL,
15.5 mol) and NaBH3CN (974 mg, 15.5 mmol) at 0 °C with stirring.
After 30 min, the mixture was made basic by addition of 5%
NaHCO3 (50 mL) and extracted with EtOAc (2 ¥ 100 mL). The ex-
tract was washed with brine (50 mL), dried (MgSO4), evaporated
under reduced pressure, and chromatographed (SiO2, 70 g, EtOAc/
MS: m/z = 275 (M+), 91 (100%).
HRMS: m/z calcd for C15H17NO4 (M+) 275.1156. Found: 275.1175.
Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C,
65.75; H, 6.37; N, 4.80.
Conversion of the Acetate (R)-10 into the Alcohol (R)-9
30
hexane, 1:2) to give the allyl alcohol (S)-2 (1.2 g, 61%), [a]D
A solution of (R)-10 (31 mg, 0.11 mmol) in MeOH (2 mL) was
stirred with K2CO3 (80 mg, 0.57 mmol) at r.t. for 2 h. After evapo-
ration of the solvent under reduced pressure the residue was diluted
with EtOAc (40 mL) and the solution was washed with brine
(5 mL), dried (MgSO4), and evaporated under reduced pressure.
The residue was chromatographed (SiO2, 6 g, EtOAc/hexane, 1:2)
-67.0 (c 0.96, CHCl3), as a colorless oil. The enantiomeric excess
of (S)-2 was determined as 99% ee by HPLC using a column with a
chiral stationary phase (CHIRALCEL OD, elution with 10% Pri-
OH-hexane).
IR (film): n = 3414, 1698 cm-1.
1H NMR (300 MHz, CDCl3): d = 7.31 (s, 5H), 5.99-5.73 (m, 2H),
5.16 (s, 2H), 4.33-3.97 (m, 2H), 3.96-3.78 (m, 1H), 3.78-3.50 (m,
2H), 2.02 (m, 1H).
29
to give the alcohol (R)-9 (23.6 mg, 95%), [a]D -7.14 (c 0.91,
CHCl3). Spectral data were identical to those of (S)-9.
Conversion of the Alcohol (S)-9 into the Acetate (S)-10
MS: m/z = 233 (M+), 91 (100%).
To a stirred solution of (S)-9 (157 mg, 0.67 mmol) in CH2Cl2 (3.5
mL) were added Et3N (0.34 mL, 2.41 mmol), 4-N,N-dimethylami-
nopyridine (DMAP) (2 mg, 0.01 mmol), and acetic anhydride (0.23
mL, 1.68 mmol) at 0 °C, and the mixture was stirred at r.t. for 40
min. The mixture was diluted with CH2Cl2 (30 mL) and was washed
successively with 5% NaHCO3 (5 mL) and brine (5 mL), dried
(MgSO4), evaporated under reduced pressure, and chromato-
graphed (SiO2, 10 g, EtOAc/hexane, 1:2) to give the acetate (S)-10
(158 mg, 86%), [a]D29 -13.0 (c 1.04, CHCl3), as a colorless oil.
HRMS: m/z calcd for C13H15NO3 (M+) 233.1051. Found: 233.1048.
Conversion of the Alcohol (S)-2 into the Acetate (S)-14
To a stirred solution of (S)-2 (63 mg, 0.27 mmol) in CH2Cl2 (2 mL)
were added Et3N (0.14 mL, 0.97 mmol), 4-N,N-dimethylaminopy-
ridine (2 mg, 0.01 mmol), and acetic anhydride (0.06 mL, 0.68
mmol) at 0 °C, and the mixture was stirred at r.t. for 1 h. The mix-
ture was diluted with CH2Cl2 (40 mL) and was washed successively
with 5% NaHCO3 (10 mL) and brine (10 mL), dried (MgSO4),
Synthesis 2000, No. 4, 521–524 ISSN 0039-7881 © Thieme Stuttgart · New York

524
H. Sakagami, K. Ogasawara
PAPER
evaporated under reduced pressure, and chromatographed (SiO2, 10
g, EtOAc/hexane, 1:4) to give the acetate (S)-14 (72 mg, 97%),
[a]D29 -114.8 (c 1.00, CHCl3).
IR (film): n = 1695 cm-1.
1H NMR (500 MHz, CDCl3): d = 7.47 (s, 5H), 6.60-5.82 (m, 2H),
5.29-5.05 (m, 2H), 4.32-4.14 (m, 1H), 3.96-3.78 (m, 2H), 3.59-
3.48 (dd, 1H, J = 13.9, 4.0 Hz), 2.07-1.93 (m, 3H).
EtOAc/hexane, 1:3) to give the crude benzoate (110 mg) as a pale
yellow oil.
The crude benzoate was dissolved in MeOH (2 mL) containing so-
dium methoxide, prepared in situ from Na (15 mg, 0.63 mol) in the
same flask, at 0 °C and stirred at r.t. for 20 min. After quenching the
reaction by addition of 5% NaHCO3 (20 mL), the mixture was ex-
tracted with CH2Cl2 (40 mL). The extract was washed with brine,
dried (MgSO4), evaporated under reduced pressure, and chromato-
graphed (SiO2, 30 g, EtOAc/hexane, 1:2) to give (S)-2 (47 mg, 96%
in 2 steps) as a colorless oil. The spectral data were identical with
those of (R)-2, but enantiomeric excess was determined as 89.4% ee
by HPLC using a column with a chiral stationary phase (CHIRAL-
CEL OD, 10% PriOH/hexane).
MS: m/z = 215 (M+-50), 91 (100%).
HRMS: m/z calcd for C13H13NO2 (M+) 215.0946. Found: 215.0939.
Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C,
65.28; H, 6.09; N, 5.11.
Resolution of Racemic N-Carbobenzoxy-3-hydroxy-1,2,3,6-tet-
rahydropyridine (±)-2
Acknowledgement
A stirred mixture of the racemic alcohol (±)-2 (1.68 g, 7.21 mmol),
vinyl acetate (3.3 mL, 35.8 mmol) in CH2Cl2 (80 mL) was suspend-
ed with immobilized lipase, Lipase PS (Pseudomonas sp., Amano)
(1.62 g), and the suspension was stirred at 40 °C for 29 h. The mix-
ture, after filtration through a Celite pad, was evaporated under re-
duced pressure and chromatographed (SiO2, 150 g, EtOAc/hexane,
1:3~1) to give the acetate (S)-14 (921 mg, 46.5%), [a]D30 -115.5 (c
0.96, CHCl3), as a colorless oil, and the alcohol (R)-2 (800 mg,
47.6%), [a]D27+65.9 (c 0.87, CHCl3), as a colorless oil. Spectral data
of the products were identical to those of (S)-2 and (S)-14, respec-
tively.
We thank the Japan Society for the Promotion of Science for a fel-
lowship (to H. S.).
References and Notes
(1) Imanishi, T.; Shin, H.; Hanaoka, M.; Momose, T.; Imanishi, I.
Chem. Pharm. Bull. 1982, 30, 3617.
Imanishi, T.; Miyashita, K.; Nakai, A.; Inoue, M.; Hanaoka,
M. Chem. Pharm. Bull. 1983, 31, 1191.
(2) Ziegler, F. E.; Bennett, G. B. J. Am. Chem. Soc. 1971, 93,
5930.
Ziegler, F. E.; Bennett, G. B. J. Am. Chem. Soc. 1973, 95,
7458.
(3) A part of the present synthesis was reported in preliminary
form: (a) Sakagami, H.; Kamikubo, T.; Ogasawara, K. Chem.
Commun. 1996, 1433.
The enantiomeric excess of the acetate (S)-14 was determined as
99% ee by HPLC using a column with a chiral stationary phase
(CHIRALCEL OD, 10% PriOH/hexane: tR = 20.5 min for (S)-2 and
28.3 min for (R)-2 at 0.5 mL/min) after transformation into the al-
cohol (S)-2 by methanolysis.
The enantiomeric excess of the alcohol (R)-2 was determined as
>99% ee by HPLC using a column with a chiral stationary phase
(CHIRALCEL OD, elution with 10% PriOH/hexane).
(b) Sakagami, H.; Kamikubo, T.; Ogasawara, K. Synlett 1997,
221.
(c) Sakagami, H.; Samizu, K.; Kamikubo, T.; Ogasawara, K.
Synlett 1996, 163.
Conversion of the Acetate (S)-14 into the Alcohol (S)-2
A solution of (S)-14 (1.26 g, 4.36 mmol) in MeOH (15 mL) was
stirred with K2CO3 (903 mg, 6.54 mmol) at r.t. for 1.75 h., and the
mixture, after filtration through a Celite pad, was evaporated under
reduced pressure. The residue was diluted with EtOAc (100 mL)
and the solution was washed with brine (30 mL), dried (MgSO4),
and evaporated under reduced pressure. The residue was chromato-
graphed (SiO2, 30 g, EtOAc/hexane, 1:2) to give the alcohol (S)-2
(990 mg, 97%), [a]D27 -67.0 (c 0.9, CHCl3). The spectral data were
identical to those of (R)-2.
(4) For a pertinent monograph, see: Wong, C. -H.; Whitesides,
G. M. Enzymes in Synthetic Organic Chemistry; Pergamon
Press: Oxford, 1994.
(5) Fowler, F. W. J. Org. Chem. 1972, 37, 1321.
(6) Mitsunobu, O. Synthesis 1981, 1.
Hughs, D. L. Org. React. 1992, 42, 335.
(7) Ushikoba, K. Nippon Seirigaku Zasshi 1959, 21, 616.
(8) Takano, S.; Yanase, M.; Sekiguchi, Y.; Ogasawara, K.
Tetrahedron Lett. 1987, 28, 1783.
(9) Shono, T.; Matsumura, Y.; Onomura, O.; Yamada, Y.
Tetrahedron Lett. 1987, 28, 4073.
Inversion of the Alcohol (R)-2 into the Enantiomer (S)-2
(10) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
To a stirred solution of (R)-2 (>99% ee) (49 mg, 0.21 mmol) in THF
(2 mL) were added Ph3P (66 mg, 0.25 mmol), DIAD (0.04 mL,
0.25 mmol), and 4-nitrobenzoic acid (0.07 mL, 1.27 mmol) at 0 °C.
After stirring at r.t. for 30 min, the mixture was evaporated under re-
duced pressure and the residue was chromatographed (SiO2, 20 g,
Article Identifier:
1437-210X,E;2000,0,04,0521,0524,ftx,en;F07499SS.pdf
Synthesis 2000, No. 4, 521–524 ISSN 0039-7881 © Thieme Stuttgart · New York