Stereoselective reactions. XXXIIII. Design and synthesis of chiral bidentate amines having a bulky group on the chiral carbon.

Article abstract of DOI:10.1248/cpb.49.330

Based on the solution structures of chiral bidentate lithium amides ((R)-3a,b) having a phenyl group on the chiral carbon, chiral bidentate amines ((R)-5a,b-8a,b and (S)-9a,b) having a bulkier group instead of a phenyl group on the chiral carbon were designed and synthesized.

Full text of DOI:10.1248/cpb.49.330

330
Notes
Chem. Pharm. Bull. 49(3) 330—334 (2001)
Vol. 49, No. 3
Stereoselective Reactions. XXXIII.1) Design and Synthesis of Chiral
Bidentate Amines Having a Bulky Group on the Chiral Carbon
a
a
,b
*
Masaharu TORIYAMA, Norio TOKUTAKE, and Kenji KOGA
College of Pharmacy, Nihon University,a Narashinodai, Funabashi-shi, Chiba 274–8555, Japan and Research and
Education Center for Materials Science, Nara Institute of Science and Technology,b Takayama-cho, Ikoma-shi, Nara 630–
0101, Japan. Received October 26, 2000; accepted December 21, 2000
Based on the solution structures of chiral bidentate lithium amides ((R)-3a,b) having a phenyl group on the
chiral carbon, chiral bidentate amines ((R)-5a,b—8a,b and (S)-9a,b) having a bulkier group instead of a phenyl
group on the chiral carbon were designed and synthesized.
Key words chiral amine; chiral lithium amide; chiral amide nitrogen; enantioselective deprotonation
Conversion of carbonyl compounds into their enolates is a for enantioselective deprotonation. Based on this considera-
fundamental and widely used process in synthetic organic tion, the present paper describes the synthesis of chiral di-
chemistry, because enolates play a central role as carbon nu- amines ((R)-5a,b—(R)-8a,b and (S)-9a,b) for the prepara-
cleophiles to undergo reactions with various electrophiles.2) tion of their corresponding lithium amides to use for enan-
In recent years, enantioselective deprotonation of prochiral tioselective deprotonation.
cyclic ketones by chiral lithium amides to give the corre-
Chiral diamines ((R)-5a,b—(R)-7a,b and (S)-9a,b) were
sponding chiral lithium enolates has become one of the use- prepared as shown in Chart 2. Thus, Z-derivatives ((R)-10—
ful methods for asymmetric synthesis.3) We have previously
reported enantioselective deprotonation of prochiral 4-substi-
tuted cyclohexanones (1) using chiral lithium amides in the
presence of excess trimethylsilyl chloride (TMSCl)4) to iso-
late the corresponding lithium enolates as trimethylsilyl enol
ethers (2).1,5) Among various chiral lithium amides examined,
it is shown that the bidentate amides ((R)-3a,b) having a
phenyl group on the chiral carbon and a neopentyl or trifluo-
roethyl group on the amide nitrogen gave the products ((R)-
2) in high ee’s.5b,c,i,l) By X-ray and NMR studies, it is also
shown that these amides ((R)-3a,b) exist almost entirely as a
chelated monomeric form (4) having a chiral amide nitrogen
in tetrahydrofuran (THF) or dimethoxyethane (DME), and in
THF, DME, ether, or toluene in the presence of 2 equivalents
of hexamethylphosphoric triamide (HMPA).5b,c,i,l) Assuming
that the substituent on the amide nitrogen and the phenyl
group on the chiral carbon in the chelated ring are trans due
to steric repulsion between them, bidentate lithium amides
(5—9) having a bulkier substituent instead of a phenyl group
Chart 1
on the chiral carbon would be more effective as a chiral base
Chart 2
To whom correspondence should be addressed. e-mail: kkoga@ms.aist-nara.ac.jp
© 2001 Pharmaceutical Society of Japan

March 2001
331
(R)-12, (S)-13) of the corresponding optically active amino (J) are given in hertz (Hz). The following abbreviations are used: brϭbroad,
sϭsinglet, dϭdoublet, ddϭdoublet of doublets, tϭtriplet, qϭquartet, mϭ
multiplet. High resolution mass spectra (HR-MS) were recorded on a Hi-
tachi M-2000 spectrometer (EI) or a JEOL GCmate (FAB). Optical rotations
were measured on a JASCO DIP-370 digital polarimeter.
acids were condensed with piperidine to give the amides
((R)-14—(R)-16, (S)-17). After deprotection, the products
((R)-18—(R)-20, (S)-21) were reduced with lithium alu-
minum hydride to the corresponding diamines ((R)-22—(R)-
24, (S)-25). Monoalkylation at the primary amino nitrogen of
these diamines was carried out by reductive alkylation using
pivalaldehyde to give the corresponding N-neopentyl deriva-
tives ((R)-5a—(R)-7a, (S)-9a), while trifluoroacetylation fol-
lowed by reduction gave the corresponding N-trifluoroethyl
derivatives ((R)-5b—(R)-7b, (S)-9b).
(R)-3,5-Dimethylphenylglycine ((R)-31) used for the syn-
thesis of (R)-12 was prepared as shown in Chart 3. Racemic
3,5-dimethylphenylglycine, prepared from 3,5-dimethylbenz-
aldehyde6) by the Bucherer–Berges reaction, was resolved via
its N-trifluoroacetyl derivative with cinchonine. (R)-30 thus
obtained was hydrolyzed to give (R)-31. The absolute config-
uration of this amino acid was determined by X-ray analysis
of the salt of its methyl ester with (S)-10-camphorsulfonic
acid.7)
Syntheses of (R)-8a and (R)-8b were carried out as shown
in Chart 4. (R)-328) was converted to its phthaloyl derivative
((R)-33), and was treated with tert-butyl chloride and alu-
minum trichloride to give (R)-34. Dephthaloylation gave the
amine ((R)-35), which was converted to (R)-8a and (R)-8b as
described above.
Results of the deprotonation reaction of 1 using chiral
lithium amides prepared from these chiral bidentate amines
will be reported separately.
(R)-1-[N-(Benzyloxycarbonyl)-2-(1-naphthyl)glycyl]piperidine ((R)-
14) Triethylamine (4.25 g, 42 mmol) was added dropwise during 15 min to
an ice-cooled solution of (R)-10 (13.4 g, 40 mmol), piperidine (3.75 g, 44
mmol), and DEPC10) (7.98 g, 44 mmol) in N,N-dimethylformamide (DMF)
(96 ml), and the whole was stirred under ice-cooling for 30 min, and then at
room temperature overnight. The solution was diluted with a mixture of
ethyl acetate (400 ml) and benzene (200 ml), and the whole was washed suc-
cessively with water (400 mlϫ4), 2.5% aqueous HCl (200 mlϫ3), water
(400 ml), saturated aqueous NaHCO3 (200 mlϫ3), water (200 ml), and brine.
The organic layer was dried over Na2SO4 and evaporated to dryness in vacuo
to give a residue, which was purified by column chromatography (silica gel,
hexanes/AcOEtϭ2/1) to give (R)-14 (15.5 g, 96%) as a colorless oil. IR
(film) cmϪ1: 3290, 1714, 1642. [a]D25 Ϫ182° (cϭ1.31, CHCl3). 1H-NMR:
1.23—1.62 (6H, m, CH2CH2CH2), 2.99—3.17 (2H, m, half of CH2NCH2),
3.42—3.83 (2H, m, half of CH2NCH2), 5.10 (2H, q, PhCH2), 6.09 (1H, d,
Jϭ9 Hz, NH), 6.34 (1H, d, Jϭ9 Hz, Ar-CH), 7.28—8.43 (12H, m, aromatic
H). Anal. Calcd for C25H26N2O3: C, 74.60; H, 6.51; N, 6.96. Found: C,
74.77; H, 6.59; N, 6.77.
(R)-1-[N-(Benzyloxycarbonyl)-2-(2-naphthyl)glycyl]piperidine ((R)-
15) By a procedure similar to the preparation of (R)-14 described above,
(R)-15 was synthesized from (R)-11 as a pale yellow oil in 91% yield. IR
(film) cmϪ1: 3400, 3300, 1717, 1641. [a]D25 Ϫ148° (cϭ1.04, CHCl3). 1H-
NMR: 0.85—1.50 (6H, m, CH2CH2CH2), 3.20—3.74 (4H, m, CH2NCH2),
4.99, 5.12 (2H, q, Jϭ12 Hz, PhCH2), 5.75 (1H, d, Jϭ7 Hz, ArCH), 6.35 (1H,
d, Jϭ7 Hz, NH), 7.23—7.95 (12H, m, aromatic H). HR-MS m/z: 403.2024
(MHϩ) (Calcd for C25H27N2O3: 403.2021).
(R)-1-[N-(Benzyloxycarbonyl)-2-(3,5-dimethylphenyl)glycyl]piperi-
dine ((R)-16) By a procedure similar to the preparation of (R)-14 de-
scribed above, (R)-16 was synthesized from (R)-12 as a colorless oil in 97%
yield. IR (film) cmϪ1: 3300, 1713, 1635. [a]D25 Ϫ133° (cϭ1.14, CHCl3). 1H-
NMR: 1.32—1.66 (6H, m, CH2CH2CH2), 2.26 (6H, s, two CH3), 3.18—3.72
(4H, m, CH2NCH2), 5.06 (2H, PhCH2), 5.52 (1H, d, Jϭ7 Hz, ArCHN), 6.37
(1H, d, Jϭ7 Hz, NH), 6.93—7.32 (8H, m, aromatic H). HR-MS m/z:
380.2118 (Mϩ) (Calcd for C23H28N2O3: 380.2098).
Experimental
General All melting and boiling points are uncorrected. IR spectra were
recorded on a JASCO IRA-1 or a JASCO FT/IR-300E spectrometer. 1H-
NMR spectra were recorded on a JEOL GSX-400 (400 MHz), a JEOL EX-
270 (270 MHz), or a JEOL EX-90 (90 MHz) spectrometer. All spectra were
recorded in CDCl3, unless otherwise stated. The chemical shifts are given in
d (ppm) using tetramethylsilane as an internal standard. Coupling constants
(S)-1-[(N-Benzyloxycarbonyl)-2-(tert-butyl)glycyl]piperidine ((S)-17)
By a procedure similar to the preparation of (R)-14 described above, (S)-17
was synthesized from (S)-13 as a colorless oil in 94% yield. IR (film) cmϪ1
:
3300, 1710, 1630. [a]D25 ϩ13.3° (cϭ1.22, MeOH). 1H-NMR: 0.98 (9H, s,
(CH3)3C), 1.4—1.8 (6H, m, CH2CH2CH2), 3.46—3.63 (4H, m, CH2NCH2),
4.61 (1H, d, Jϭ10 Hz, tert-BuCHN), 5.05 (1H, d, Jϭ12 Hz, half of
PhCH2O), 5.12 (1H, d, Jϭ12 Hz, half of PhCH2O), 5.65 (1H, d, Jϭ10 Hz,
NHCO), 7.2—7.4 (5H, m, C6H5). Anal. Calcd for C19H28N2O3: C, 68.65; H,
8.49; N, 8.43. Found: C, 68.53; H, 8.53; N, 8.22.
(R)-1-[2-(1-Naphthyl)glycyl]piperidine ((R)-18) A solution of (R)-14
(15.7 g) in AcOH (7 ml) was mixed with a solution of 33% HBr in AcOH
(21 ml) under ice-cooling, and the whole was stirred at room temperature
overnight. The solution was poured into ice-water (200 ml), and washed with
ether (200 mlϫ3). The aqueous layer was basified by addition of NaHCO3,
Chart 3
Chart 4

332
Vol. 49, No. 3
matic H). HR-MS m/z: 233.2020 (MHϩ) (Calcd for C15H25N2: 233.2018).
(S)-1-tert-Butyl-2-(1-piperidino)ethylamine ((S)-25) By a procedure
similar to the preparation of (R)-22 described above, crude (S)-25 (13.3 g)
synthesized from (S)-21 (14.7 g, 74.1 mmol) was mixed with picric acid (ca.
80%, 45.5 g, ca. 160 mmol) in EtOH. The precipitates were collected by fil-
tration. Recrystallization from MeOH (1.2 l) gave (S)-25·dipicrate (37.3 g,
78%) as yellow prisms of mp 192—193 °C. [a]D25 ϩ72.0° (cϭ0.74, acetone).
Anal. Calcd for C23H30N8O14: C, 42.99; H, 4.71; N, 17.44. Found: C, 43.26;
H, 4.71; N, 17.62. (S)-25 was obtained from this salt as a colorless oil of
bp1.0 160—180 °C (bath temperature) after bulb-to-bulb distillation. [a]D25
and was extracted with CHCl3 (200 mlϫ3). The organic extracts were com-
bined, washed with brine, dried over K2CO3, and evaporated to dryness
in vacuo to give a residue, which was purified by column chromatography
(silica gel, CHCl3/MeOHϭ9/1) to give (R)-18 (10.1 g, 97%) as a colorless
1
oil. IR (film) cmϪ1: 3360, 1640. [a]D25 Ϫ167.5° (cϭ1.37, EtOH). H-NMR:
0.80—1.56 (6H, m, CH2CH2CH2), 2.04 (2H, s, NH2), 2.88—3.12 (2H, m,
half of CH2NCH2), 3.52—3.82 (2H, m, half of CH2NCH2), 5.41 (1H, s,
ArCHCO), 7.26—8.28 (7H, m, aromatic H). HR-MS m/z: 269.1666 (MHϩ)
(Calcd for C17H21N2O: 269.1654).
(R)-1-[2-(2-Naphthyl)glycyl]piperidine ((R)-19) By a procedure simi-
lar to the preparation of (R)-18 described above, (R)-19 was synthesized
from (R)-15 and was recrystallized from hexanes–ether as pale yellow crys-
tals of mp 80.5—81.0 °C in 90% yield. IR (KBr) cmϪ1: 3365, 1635. [a]D25
Ϫ128.5° (cϭ1.06, EtOH). 1H-NMR: 0.86—1.60 (6H, m, CH2CH2CH2), 2.08
(2H, s, NH2), 3.17—3.77 (4H, m, CH2NCH2), 4.90 (1H, s, ArCHCO),
7.44—7.88 (7H, m, aromatic H). HR-MS m/z: 269.1653 (MHϩ) (Calcd for
C17H21N2O: 269.1654).
1
ϩ90.0° (cϭ1.08, MeOH). H-NMR: 0.88 (9H, s, (CH3)3C), 1.35—1.7 (8H,
m, CH2CH2CH2, NH2), 2.06 (1H, dd, Jϭ11, 12 Hz, half of CH2N), 2.22 (1H,
dd, Jϭ2.7, 12 Hz, half of CH2N), 2.1—2.55 (4H, m, CH2NCH2), 2.62 (1H,
dd, Jϭ2.7, 12 Hz, tert-BuCH). HR-MS m/z: 185.2025 (Mϩ) (Calcd for
C11H25N2: 185.2018).
(R)-N-[1-(1-Naphthyl)-2-(1-piperidino)ethyl]trifluoroacetamide ((R)-
26) A solution of (R)-22 (2.04 g, 8 mmol) and ethyl trifluoroacetate (1.71
g, 12 mmol) in MeOH (10 ml) was stirred at room temperature overnight.
The reaction mixture was evaporated in vacuo to dryness, and the residue
was subjected to column chromatography (silica gel, hexanes/AcOEtϭ2/1)
to give (R)-26 (2.55 g, 91%) as a pale yellow oil. IR (film) cmϪ1: 3310,
1703. [a]D25 Ϫ42.5° (cϭ1.03, MeOH). 1H-NMR: 1.46—1.67 (6H, m,
CH2CH2CH2), 2.37—2.74 (4H, m, CH2NCH2), 2.89 (2H, d, Jϭ6 Hz, NCH2),
5.77 (1H, t, Jϭ7 Hz, ArCH), 7.44—8.02 (7H, m, aromatic H), 7.90—8.20
(1H, br, NH). HR-MS m/z: 351.1687 (MHϩ) (Calcd for C19H22F3N2O:
351.1684).
(R)-N-[1-(2-Naphthyl)-2-(1-piperidino)ethyl]trifluoroacetamide ((R)-
27) By a procedure similar to the preparation of (R)-26 described above,
(R)-27 was synthesized from (R)-23 in 88% yield after column chromatogra-
phy (silica gel, hexanes/AcOEtϭ2/1) followed by recrystallization from
hexanes as colorless needles of mp 106—106.5 °C. IR (KBr) cmϪ1: 3336,
1702. [a]D25 Ϫ109.5° (cϭ1.06, MeOH). 1H-NMR: 1.35—1.70 (6H, m,
CH2CH2CH2), 2.25—2.60 (4H, m, CH2NCH2), 2.68 (2H, d, Jϭ8 Hz, CH2N),
4.99 (1H, t, Jϭ8 Hz, ArCH), 7.36—7.86 (7H, m, aromatic H), 7.69—7.86
(1H, br, NH). HR-MS m/z: 351.1686 (MHϩ) (Calcd for C19H22F3N2O:
351.1684).
(R)-1-[2-(3,5-Dimethylphenyl)glycyl]piperidine ((R)-20) By a proce-
dure similar to the preparation of (R)-18 described above, (R)-20 was
synthesized from (R)-16 as a pale yellow oil in 91% yield. IR (film) cmϪ1
:
3360, 1637. [a]D25 Ϫ96.9° (cϭ1.17, EtOH). 1H-NMR: 0.90—1.64 (6H, m,
CH2CH2CH2), 2.01 (2H, s, NH2), 2.29 (6H, s, two CH3), 3.13—3.72 (4H, m,
CH2NCH2), 4.64 (1H, s, ArCHCO), 6.91 (3H, s, aromatic H). HR-MS m/z:
247.1810 (MHϩ) (Calcd for C15H23N2O: 247.1810).
(S)-1-[2-(tert-Butyl)glycyl]piperidine ((S)-21) By a procedure similar
to the preparation of (R)-18 described above, (S)-21 was synthesized from
(S)-17 as a pale yellow oil in 99%. An analytical sample was obtained by
bulb-to-bulb distillation to give a colorless oil of bp1.0 210—220 °C (bath
temperature). IR (film) cmϪ1: 1625. [a]D25 ϩ79.7° (cϭ1.04, MeOH). 1H-
NMR: 0.99 (9H, s, (CH3)3C), 1.5—2.0 (8H, m, CH2CH2CH2, NH2), 3.4—
3.8 (5H, m, CH2NCH2, t-BuCHN). HR-MS m/z: 198.1688 (Mϩ) (Calcd for
C11H22N2O: 198.1727).
(R)-1-(1-Naphthyl)-2-(1-piperidino)ethylamine ((R)-22) A solution of
(R)-18 (10.0 g, 37.3 mmol) in THF (20 ml) was added dropwise during 20
min to a suspension of LiAlH4 (6.10 g, 149 mmol) in THF (80 ml), and the
whole was stirred under reflux for 2 h. Under stirring and ice-cooling, water
(6.1 ml), 15% aqueous NaOH (6.1 ml) and water (18.3 ml) were added suc-
cessively to the reaction mixture, and the whole was filtered. The filtrate and
THF washings were combined and evaporated to dryness in vacuo to give a
pale yellow oil. The oil was dissolved in EtOH, and then excess HCl–EtOH
was added. The crystals deposited were collected and recrystallized from
EtOH to give (R)-22·2HCl (11.1 g, 91%) as colorless plates of mp 188—
189 °C. IR (KBr) cmϪ1: 3308, 1598. [a]D25 Ϫ19.4° (cϭ1.37, EtOH). This salt
(3.27 g) was dissolved in water, and the resulting solution was basified to pH
8 using NaHCO3. The whole was extracted with ether (80 mlϫ3). The ethe-
real extracts were combined, washed with brine, dried over K2CO3, and
evaporated to dryness in vacuo to give a residue, which was recrystallized
from hexane to give (R)-22 (2.30 g, 90%) as colorless plates of mp 88—
89 °C. IR (nujol) cmϪ1: 3380. [a]D25 Ϫ130.0° (cϭ1.25, MeOH). 1H-NMR:
1.44—1.72 (6H, m, CH2CH2CH2), 1.94 (2H, s, NH2), 2.39—2.70 (6H, m,
(CH2)2NCH2), 5.02 (1H, dd, Jϭ3, 10 Hz, ArCH), 7.44—8.11 (7H, m, aro-
matic H). Anal. Calcd for C17H22N2: C, 80.27; H, 8.72; N, 11.01. Found: C,
80.53; H, 8.96; N, 10.92.
(R)-1-(2-Naphthyl)-2-(1-piperidino)ethylamine ((R)-23) By a proce-
dure similar to the preparation of (R)-22 described above, crude (R)-23
(8.62 g) synthesized from (R)-19 (10.2 g, 38 mmol) was mixed with L-tar-
taric acid (5.09 g, 33.9 mmol) in EtOH. The precipitates were collected by
filtration. Recrystallization from EtOH gave (R)-23·tartarate salt (11.0 g,
72%) as colorless crystals of mp 129—130 °C. IR (KBr) cmϪ1: 3320. [a]D25
ϩ28.4° (cϭ1.04, H2O). (R)-23 was obtained from this salt as a pale yellow
oil, which solidified (mp 57.5—58 °C). IR (film) cmϪ1: 3370, 3290. [a]D25
Ϫ37.7° (cϭ1.08, MeOH). 1H-NMR: 1.37—1.70 (6H, m, CH2CH2CH2), 2.08
(2H, s, NH2), 2.27—2.70 (6H, m, (CH2)2NCH2), 4.30 (1H, dd, Jϭ4, 10 Hz,
ArCH), 7.40—7.88 (7H, m, aromatic H). HR-MS m/z: 255.1860 (MHϩ)
(Calcd for C17H23N2: 255.1861).
(R)-N-[1-(3,5-Dimethylphenyl)-2-(1-piperidino)ethyl]trifluoroacet-
amide ((R)-28) By a procedure similar to the preparation of (R)-26 de-
scribed above, (R)-28 was synthesized from (R)-24 as a colorless oil in 99%
yield. IR (film) cmϪ1: 3300, 1700. [a]D25 Ϫ80.9° (cϭ1.73, MeOH). 1H-
NMR: 1.40—1.70 (6H, m, CH2CH2CH2), 2.29 (6H, s, two ArCH3), 2.33
(2H, d, CH2N), 2.45—2.70 (4H, m, CH2NCH2), 4.73 (1H, t, Jϭ8 Hz,
ArCHN), 6.85 ((2H, s, aromatic H), 6.90 (1H, s, aromatic H), 7.6—7.9 (1H,
br, NH). HR-MS m/z: 328.1757 (Mϩ) (Calcd for C17H23F3N2O: 328.1760).
(R)-N-(2,2-Dimethylpropyl)-1-(1-naphthyl)-2-(1-piperidino)ethyl-
amine ((R)-5a) A solution of (R)-22 (2.28 g, 8.96 mmol) and pivalalde-
hyde (0.97 g, 11.2 mmol) in benzene was stirred at room temperature for 1 h.
The reaction mixture was dried over K2CO3 and evaporated to dryness in
vacuo, and the residue was dissolved in EtOH (36 ml). Under ice-cooling,
NaBH4 (0.68 g, 17.9 mmol) was added, and the whole was stirred at room
temperature for 30 min. Evaporation of the solvent in vacuo gave a residue,
which was mixed with saturated aqueous NaHCO3 (30 ml), and the whole
was extracted with hexanes (80 mlϫ3). The organic extracts were combined,
washed with brine, dried over Na2SO4, and evaporated to dryness in vacuo.
The residue was purified by column chromatography (silica gel, benzene/
etherϭ10/1) followed by bulb-to-bulb distillation to give (R)-5a (2.60 g,
89%) as a colorless oil of bp0.4 230 °C (bath temperature). IR (film) cmϪ1
:
3320. [a]D25 Ϫ148.8° (cϭ1.09, MeOH). 1H-NMR: 0.96 (9H, s, (CH3)3C),
1.44—1.66 (6H, m, CH2CH2CH2), 2.18—2.66 (9H, m, NHCH2Bu-t,
(CH2)2NCH2), 4.57 (1H, dd, Jϭ3, 11 Hz, ArCH), 7.3—8.2 (7H, m, aromatic
H). HR-MS m/z: 325.2650 (MHϩ) (Calcd for C22H33N2: 325.2644).
(R)-N-(2,2-Dimethylpropyl)-1-(2-naphthyl)-2-(1-piperidino)ethyl-
amine ((R)-6a) By a procedure similar to the preparation of (R)-5a de-
scribed above, (R)-6a was synthesized from (R)-23 in 85% yield as colorless
needles of mp 104.5—105 °C after recrystallization from MeOH. IR (KBr)
cmϪ1: 3290. [a]D25 Ϫ94.2° (cϭ1.03, MeOH). 1H-NMR: 0.93 (9H, s,
(CH3)3C), 1.30—1.68 (6H, m, CH2CH2CH2), 2.12 (1H, br, NH), 2.21 (1H, d,
Jϭ11 Hz, half of CH2Bu-t), 2.26 (1H, Jϭ11 Hz, half of CH2Bu-t), 2.26—
2.40 (2H, m, half of CH2NCH2), 2.35 (1H, dd, Jϭ4, 12 Hz, half of CH2N),
2.43—2.65 (2H, m, half of CH2NCH2), 2.49 (1H, dd, Jϭ11, 12 Hz, half of
CH2N), 3.84 (1H, dd, Jϭ4, 11 Hz, ArCH), 7.37—7.90 (7H, m, aromatic H).
HR-MS m/z: 325.2642 (MHϩ) (Calcd for C22H33N2: 325.2644).
(R)-1-(3,5-Dimethylphenyl)-2-(1-piperidino)ethylamine ((R)-24) By a
procedure similar to the preparation of (R)-23 described above, (R)-24·L-
tartarate salt was synthesized from (R)-20 as colorless crystals of mp 106—
107 °C (from EtOH) in 75% yield. IR (nujol) cmϪ1: 3375. [a]D25 Ϫ6.8°
(cϭ1.14, MeOH). (R)-24 was obtained from this salt as a colorless solid of
1
mp 52—53 °C. IR (nujol) cmϪ1: 3330. [a]D25 Ϫ44.2° (cϭ1.26, MeOH). H-
NMR: 1.40—1.70 (6H, m, CH2CH2CH2), 1.99 (2H, s, NH2), 2.31 (6H, s,
two ArCH3), 2.20—2.50 (4H, m, CH2NCH2), 2.52—2.63 (2H, m, NCH2),
4.62 (1H, dd, Jϭ4, 10 Hz, ArCH), 6.88 (1H, s, aromatic H), 6.99 (2H, s, aro-
(R)-N-(2,2,Dimethylpropyl)-1-(3,5-dimethylphenyl)-2-(1-piperidino)-
ethylamine ((R)-7a) By a procedure similar to the preparation of (R)-5a

March 2001
333
described above, (R)-7a was synthesized from (R)-24 in 73% yield after ArCH3), 5.50 (1H, s, ArCH), 6.98 (2H, s, aromatic H), 7.03 (1H, s, aromatic
bulb-to-bulb distillation as a colorless oil of bp3 270 °C (bath temperature). H), 7.16 (1H, br, NH), 6.80—7.40 (1H, br, CO2H). Anal. Calcd for
IR (film) cmϪ1: 3310. [a]D25 Ϫ92.6° (cϭ1.07, MeOH). 1H-NMR: 0.93 (9H, s, C12H12F3NO3: C, 52.37; H, 4.39; N, 5.09. Found: C, 52.42; H, 4.28; N, 5.20.
(CH3)3C), 1.40—1.70 (6H, m, CH2CH2CH2), 2.30 (6H, s, two ArCH3),
(R)-N-(Trifluoroacetyl)-2-(3,5-dimethylphenyl)glycine ((R)-30) A so-
2.05—2.65 (9H, m, NHCH2Bu-t, (CH2)2NCH2), 3.61 (1H, dd, Jϭ4, 11 Hz, lution of (RS)-30 (137.6 g, 0.50 mol) and cinchonine (147.2 g, 0.50 mol) in
ArCH), 6.86 (1H, s, aromatic H), 7.00 (2H, s, aromatic H). Anal. Calcd for EtOH (800 ml) was heated under reflux for 30 min, and the whole was evap-
C20H34N2: C, 79.41; H, 11.33; N, 9.26. Found: C, 79.59; H, 11.32; N, 9.42.
orated to dryness in vacuo. The residue was recrystallized from ether to give
(S)-N-(2,2-Dimethylpropyl)-1-tert-butyl-2-(1-piperidino)ethylamine a colorless solid (125.3 g), which was recrystallized from benzene–ether to
((S)-9a) By a procedure similar to the preparation of (R)-5a described give colorless crystals (88.5 g, 62%) of mp 178.5—179.5 °C. [a]D25 ϩ25.7°
above, (S)-9a was synthesized from (S)-25 in 77% yield after recrystalliza- (cϭ1.66, EtOH). This salt was mixed with 2.5% aqueous HCl (400 ml), and
tion from MeOH as colorless needles of mp 30—30.5 °C, which were fur- the whole was extracted with ether (200 mlϫ3). The organic extracts were
ther purified by bulb-to-bulb distillation. IR (KBr) cmϪ1: 3316. [a]D25 ϩ79.0° combined, washed with water (100 mlϫ2), brine, dried over Na2SO4, and
1
(cϭ1.13, MeOH). H-NMR: 0.86 (9H, s, (CH3)3C), 0.91 (9H, s, (CH3)3C), evaporated to dryness in vacuo. The residue was recrystallized from ben-
1.32—1.62 (7H, m, CH2CH2CH2, NH), 2.06—2.56 (9H, m, (CH2)2NCH2,
tert-BuCHNCH2). HR-MS m/z: 255.2799 (MHϩ) (Calcd for C16H35N2: 147 °C. [a]D25 Ϫ170.2° (cϭ1.27, MeOH). 1H-NMR spectral data were identi-
255.2800). cal to those of (RS)-30 described above. Methyl ester: A solution of CH2N2
(R)-N-(2,2,2-Trifluoroethyl)-1-(1-naphthyl)-2-(1-piperidino)ethylamine in ether was added to a solution of (R)-30 (83 mg) in ether (1 ml) until the
((R)-5b) A 1 M solution of BH3 in THF (20 ml, 20 mmol) was added drop- color of the resulting solultion was kept pale yellow. After addition of acetic
zene–ether to give (R)-307) (38.4 g, 56%) as colorless crystals of mp 146—
wise to a solution of (R)-26 (1.66 g, 4.74 mmol) in THF (6 ml), and the acid to decompose excess CH2N2, ether (30 ml) was added. The resulting so-
whole was heated under reflux for 8 h. The reaction mixture was quenched lution was washed successively with saturated aqueous NaHCO3 (5 mlϫ2),
with MeOH (16 ml) under ice-cooling, and was then evaporated to dryness water (5 ml), brine, and dried over Na2SO4. Evaporation of the solvent gave
in vacuo. The residue was mixed with 37% HCl–MeOH (20 ml), and the
the methyl ester of (R)-30 (85 mg, 98%) as a colorless solid of mp 98—
whole was stirred at room temperature for 1 h. Evaporation of the solvent 98.5 °C. Optical purity of this sample was found to be 96.3% by HPLC
gave a residue, which was mixed with saturated aqueous NaHCO3, and the
analysis using a Daicel CHIRALPAC AD column. IR (nujol) cmϪ1: 3325,
whole was extracted with hexanes (80 mlϫ3). The organic extracts were 1732, 1712. 1H-NMR: 2.32 (6H, s, Ar(CH3)2), 3.77 (3H, s, OCH3), 5.47 (1H,
combined, washed with brine, dried over Na2SO4, and evaporated to dryness d, Jϭ7 Hz, ArCH), 6.95 (2H, s, aromatic H), 7.00 (1H, s, aromatic H), 7.29
in vacuo to give an oil. Purification by column chromatography (silica gel, (1H, br, NH). HR-MS m/z: 289.0927 (Mϩ) (Calcd for C13H14F3NO3:
hexanes/etherϭ5/1) followed by bulb-to-bulb distillation gave (R)-5b (1.45 289.0926).
g, 91%) as a colorless oil of bp0.1 210 °C (bath temperature). IR (film) cmϪ1
:
(R)-N-2-(3,5-Dimethylphenyl)glycine ((R)-31) A mixture of (R)-30
3310. [a]D25 Ϫ149.2° (cϭ1.13, MeOH). 1H-NMR: 1.44—1.73 (6H, m, (37.5 g) and 10% aqueous HCl (540 ml) was heated under reflux for 1 h.
CH2CH2CH2), 2.35—2.68 (6H, m, (CH2)2NCH2), 3.07—3.16 (3H, m, Under ice-cooling, 10% aqueous NaOH was added to the resulting solution
NHCH2CF3), 4.86 (1H, dd, Jϭ3, 10 Hz, ArCH), 7.44—8.13 (7H, m, aro- to pH 6.0. The precipitates were collected by filtration and washed with
matic H). Anal. Calcd for C19H23F3N2: C, 67.84; H, 6.89; N, 8.33. Found: C, water, EtOH, and ether successively to give (R)-31 (19.6 g, 80%) as a color-
68.03; H, 6.81; N, 8.47.
less powder of mp Ͼ220 °C. [a]D25 Ϫ135.3° (cϭ1.25, 1 N HCl). 1H-NMR
(R)-N-(2,2,2-Trifluoroethyl)-1-(2-naphthyl)-2-(1-piperidino)ethylamine (DMSO-d6): 2.25 (6H, s, two ArCH3), 4.18 (1H, s, ArCH), 6.93 (1H, s, aro-
((R)-6b) By a procedure similar to the preparation of (R)-5b described matic H), 7.01 (2H, s, aromatic H). HR-MS m/z: 180.1027 (MHϩ) (Calcd
above, (R)-6b was synthesized from (R)-27 and was recrystallized from for C10H14NO2: 180.1024).
MeOH as colorless crystals of mp 98.5—99 °C in 89% yield. IR (KBr)
(R)-N-Phthaloyl-1-phenyl-2-(1-piperdino)ethylamine ((R)-33) A so-
lution of (R)-328) (22.2 g, 109 mmol) and phthalic anhydride (19.3 g, 130
mmol) in AcOH (135 ml) was heated under reflux for 2.5 h. After cooling,
AcOEt (200 ml) was added, and the whole was extracted with 5% aqueous
1
cmϪ1: 3295. [a]D25 Ϫ81.7° (cϭ1.03, MeOH). H-NMR: 1.40—1.70 (6H, m,
CH2CH2CH2), 2.20—2.40 (2H, m, half of CH2NCH2), 2.35 (1H, dd, Jϭ3,
12 Hz, half of CH2N), 2.51 (1H, dd, Jϭ11, 12 Hz, half of CH2N), 2.55—2.70
(2H, m, half of CH2NCH2), 2.90—3.08 (1H, br, NH), 3.09 (2H, q, Jϭ10 Hz, HCl (550 mlϫ3, 100 mlϫ2). The aqueous extracts were combined, made al-
CH2CF3), 4.12 (1H, dd, Jϭ3, 11 Hz, ArCH), 7.42—7.93 (7H, m, aromatic kaline by addition of K2CO3, and the whole was extracted with AcOEt (200
H). HR-MS m/z: 337.1894 (MHϩ) (Calcd for C19H24F3N2: 337.1891).
(R)-N-(2,2,2-Trifluoroethyl)-1-(3,5-dimethylphenyl)-2-(1-piperidino)-
mlϫ3). The organic extracts were combined, washed with water (200
mlϫ3), brine, dried over Na2SO4, and evaporated to dryness in vacuo. The
ethylamine ((R)-7b) By a procedure similar to the preparation of (R)-5b residue was purified by column chromatography (silica gel, hexanes/
described above, (R)-7b was synthesized from (R)-28 as a colorless oil of AcOEtϭ2/1), followed by recrystallization from hexanes to give (R)-33
bp3 230 °C (bath temperature) in 88% yield. IR (film) cmϪ1: 3315. [a]D25 (27.3 g, 75%) as pale yellow crystals of mp 84.5—85 °C. IR (nujol) cmϪ1
:
1
Ϫ77.0° (cϭ1.26, MeOH). 1H-NMR: 1.35—1.70 (6H, m, CH2CH2CH2), 2.31 1770, 1712. [a]D25 Ϫ38.4° (cϭ1.22, CHCl3). H-NMR: 1.20—1.53 (6H, m,
(6H, s, two ArCH3), 2.10—2.65 (6H, m, (CH2)2NCH2), 3.06 (2H, q, Jϭ10, CH2CH2CH2), 2.25—2.66 (4H, m, CH2NCH2), 2.76 (1H, dd, Jϭ5, 13 Hz,
CH2CF3), 2.80—3.10 (1H, br, NH), 3.88 (1H, dd, Jϭ3, 11 Hz, ArCH), 6.90
half of PhCCH2N), 3.67 (1H, dd, Jϭ12, 13 Hz, half of PhCCH2N), 5.56 (1H,
(1H, s, aromatic H), 6.97 (2H, s, aromatic H). HR-MS m/z: 314.1956 (Mϩ) dd, Jϭ5, 12 Hz, PhCH), 7.23—7.85 (9H, m, aromatic H). Anal. Calcd for
(Calcd for C17H25F3N2: 314.1968).
C21H22N2O2: C, 75.42; H, 6.63; N, 8.38. Found: C, 75.43; H, 6.70; N, 8.39.
(S)-N-(2,2,2-Trifluoroethyl)-1-tert-butyl-2-(1-piperidino)ethylamine
(R)-N-Phthaloyl-1-(3,5-di-tert-butylphenyl)-2-(1-piperidino)ethylamine
((S)-9b) By a procedure similar to the preparation of (R)-5b described ((R)-34) Under ice-cooling, AlCl3 (60.0 g, 450 mmol) was added in por-
above, (S)-9b was synthesized from (S)-29 as a colorless oil of bp1.5 160 °C tions during 30 min to a solution of (R)-33 (15.1 g, 45 mmol) in tert-BuCl
1
(bath temperature) in 87% yield. [a]D25 ϩ66.4° (cϭ0.90, MeOH). H-NMR: (300 ml), and the whole was stirred for 1 h. After addition of 5% aqueous
0.89 (9H, s, (CH3)3C), 1.35—1.63 (6H, m, CH2CH2CH2), 1.66 (1H, br, NH),
HCl (400 ml) under ice-cooling, the whole was washed with hexanes (200
2.12 (1H, dd, Jϭ10, 12 Hz, half of tert-BuCCH2N), 2.15—2.27 (2H, m, half mlϫ3). The aqueous layer and insoluble precipitates were combined, made
of CH2NCH2), 2.28—2.40 (2H, m, CH2N and half of tert-BuCCH2N), alkaline by addition of aqueous NaOH, and the whole was extracted with
2.40—2.57 (2H, m, half of CH2NCH2), 3.21 (1H, dq, Jϭ10, 14 Hz, half of AcOEt (200 mlϫ2). The organic extracts were combined, washed with water
CH2CF3), 3.42 (1H, dq, Jϭ10, 14 Hz, half of CH2CF3). HR-MS m/z: (200 mlϫ3) and brine, and dried over K2CO3. Evaporation of the solvent
266.1931 (Mϩ) (Calcd for C13H25F3N2: 266.1964).
gave a residue, which was purified by column chromatography (silica gel,
(RS)-N-(Trifluoroacetyl)-2-(3,5-dimethylphenyl)glycine ((RS)-30)
A
hexanes/AcOEtϭ4/1) to give (R)-34 (7.2 g, 36%) as a pale yellow oil. This
solution of (RS)-3,5-dimethylphenylglycine (88.8 g, 0.496 mol), triethy- was used for the next step without further purification. IR (film) cmϪ1: 1767,
lamine (100.4 g, 0.99 mol), and ethyl trifluoroacetate (84.6 g, 0.595 mol) in 1710. [a]D25 Ϫ20.9° (cϭ1.13, CHCl3). 1H-NMR: 1.32 (18H, s, two (CH3)3C),
MeOH (600 ml) was stirred at room temperature for 24 h. Evaporation of the 1.02—1.46 (6H, m, CH2CH2CH2), 2.26—2.64 (4H, m, CH2NCH2), 2.69
solvent gave a residue, which was mixed with 5% aqueous HCl (400 ml), (1H, dd, Jϭ5, 13 Hz, half of ArCCH2N), 3.75 (1H, dd, Jϭ12, 13 Hz, half of
and the whole was extracted with ether (300 mlϫ3). The organic extracts ArCCH2N), 5.53 (1H, dd, Jϭ5, 12 Hz, ArCH), 7.34—7.83 (7H, m, aromatic
were combined, washed with 5% aqueous HCl (100 ml), water (100 mlϫ3), H). HR-MS m/z: 447.3010 (MHϩ) (Calcd for C29H39N2O2: 447.3011).
and brine. The organic phase was dried over Na2SO4 and evaporated to dry-
(R)-1-(3,5-Di-tert-butylphenyl)-2-(1-piperidino)ethylamine ((R)-35)
ness in vacuo to give a residue, which was recrystallized from benzene– A solution of (R)-34 (13.4 g, 30 mmol) and hydrazine hydrate (2.63 g, 42
ether to give (RS)-30 (105.5 g, 77%) as colorless crystals of mp 173.5— mmol) in EtOH (270 ml) was heated under reflux for 1.5 h. After cooling,
174.5 °C. IR (KBr) cmϪ1: 3342, 1723, 1689. 1H-NMR: 2.32 (6H, s, two
6 N aqueous HCl (22 ml) was added, and the whole was heated under reflux

334
Vol. 49, No. 3
for 30 min. The precipitates were filtered off, and the filtrate was evaporated
to dryness in vacuo. The residue was mixed with water (100 ml), and washed
with CHCl3 (50 mlϫ3). The aqueous layer was basified by addition of aque-
ous ammonia, and extracted with CHCl3 (80 mlϫ4). The organic extracts
were combined, washed with brine, dried over K2CO3, and evaporated to
dryness in vacuo. The residue was subjected to column chromatography (sil-
ica gel, CHCl3/MeOHϭ9/1) to give a pale yellow solid. This solid was
treated with HCl–MeOH to give a solid, which was recrystallized from
EtOH–ether to give (R)-35·2HCl (9.2 g, 79%) as colorless crystals of mp
214—215 °C. [a]D25 ϩ10.2° (cϭ1.06, MeOH). This salt (7.90 g) was dis-
solved in water, and the resulting solution was basified by addition of
K2CO3, and the whole was extracted with ether (80 mlϫ3). The organic ex-
tracts were combined, washed with water (80 mlϫ2) and brine, dried over
K2CO3, and evaporated to dryness in vacuo. The residue was recrystallized
from hexanes to give (R)-35 (4.94 g, 77% recovery) as colorless plates of mp
74—75 °C. IR (KBr) cmϪ1: 3380. [a]D25 Ϫ30.8° (cϭ1.12, MeOH). 1H-NMR:
1.33 (18H, s, two (CH3)3C), 1.40—1.70 (6H, m, CH2CH2CH2), 1.94 (2H, s,
NH2), 2.30—2.50 (4H, m, CH2NCH2), 2.53—2.70 (2H, m, ArCCH2N), 4.13
(1H, dd, Jϭ4, 11 Hz, ArCH), 7.22 (2H, d, Jϭ1.8 Hz, aromatic H), 7.31 (1H,
s, aromatic H). HR-MS m/z: 317.2959 (MHϩ) (Calcd for C21H37N2:
317.2955).
(R)-N-[1-(3,5-Di-tert-butylphenyl)-2-(1-piperidino)ethyl]trifluoroacet-
amide ((R)-36) A solution of (R)-35 (3.12 g, 9.86 mmol) and ethyl trifluo-
roacetate (2.10 g, 14.8 mmol) in MeOH (30 ml) was stirred at room tempera-
ture for 4 h, and the whole was evaporated to dryness in vacuo. The residue
was subjected to column chromatography (silica gel, hexanes/AcOEtϭ4/1)
to give a colorless oil, which was recrystallized from hexanes to give (R)-36
(3.21 g, 77%) as colorless needles of mp 115—116 °C. IR (KBr) cmϪ1: 3300,
1703. [a]D25 Ϫ77.7° (cϭ1.16, MeOH). 1H-NMR: 1.31 (18H, s, two (CH3)3C),
1.40—1.67 (6H, m, CH2CH2CH2), 2.23—2.37 (2H, m, ArCCH2N), 2.42—
2.66 (4H, m, CH2NCH2), 4.85 (1H, dd, Jϭ6, 9 Hz, ArCH), 7.05 (2H, d,
Jϭ1.8 Hz, aromatic H), 7.32 (1H, t, Jϭ1.8 Hz, aromatic H), 7.50—7.74 (1H,
br, CONH). Anal. Calcd for C23H35F3N2O: C, 66.96; H, 8.55; N, 6.79.
Found: C, 67.09; H, 8.71; N, 6.76.
(R)-N-(2,2-Dimethylpropyl)-1-(3,5-di-tert-butylphenyl)-2-(1-piperidino)-
ethylamine ((R)-8a) By a procedure similar to the preparation of (R)-5a
described above, (R)-8a was synthesized from (R)-35 as colorless needles
(from MeOH) of mp 96—97 °C in 79% yield. IR (KBr) cmϪ1: 3318. [a]D25
Ϫ83.7° (cϭ1.02. MeOH). 1H-NMR: 0.94 (9H, s, (CH3)3C), 1.32 (18H, s,
two (CH3)3CAr), 1.40—1.67 (6H, m, CH2CH2CH2), 2.14—2.60 (9H, m,
CH2NCH2, ArCCH2N, tert-BuCH2N, NH), 3.67 (1H, dd, Jϭ4, 11 Hz,
ArCH), 7.23 (2H, d, Jϭ1.8 Hz, aromatic H), 7.27 (1H, t, Jϭ1.8 Hz, aromatic
H). Anal. Calcd for C26H46N2: C, 80.76; H, 11.99; N, 7.25. Found: C, 81.00;
H, 12.14; N, 7.26.
(R)-N-(2,2,2-Trifluoroethyl)-1-(3,5-di-tert-butylphenyl)-2-(1-piperidino)-
ethylamine ((R)-8b) By a procedure similar to the preparation of (R)-5b
described above, (R)-8b was synthesized from (R)-36 as a colorless oil of
bp0.2 230 °C (bath temperature) in 94% yield. IR (film) cmϪ1: 3322. [a]D25
Ϫ69.3° (cϭ1.24, MeOH). 1H-NMR: 1.32 (18H, s, two (CH3)3C), 1.40—1.70
(6H, m, CH2CH2CH2), 2.20—2.70 (6H, CH2NCH2, ArCCH2N), 2.85—3.16
(3H, m, CH2CF3, NH), 3.91 (1H, dd, Jϭ3, 11 Hz, ArCH), 7.20 (2H, d,
Jϭ1.8 Hz, aromatic H), 7.32 (1H, t, Jϭ1.8 Hz, aromatic H). HR-MS m/z:
399.2986 (MHϩ) (Calcd for C23H38F3N2: 399.2987).
(2000).
2) a) Carey F. A., Sundberg R. J., “Advanced Organic Chemistry, Part B,
Reactions and Synthesis,” Plenum Press, New York, 1990, Chapters 1
and 2; b) Mekelburger H. B., Wilcox C. S., “Comprehensive Organic
Synthesis,” Vol. 2, ed. by Trost B. M., Fleming I., Pergamon Press,
Oxford, 1991, Chapter 1.4; c) Caine D., “Comprehensive Organic Syn-
thesis,” Vol. 3, ed. by Trost B. M., Fleming I., Pergamon Press, Ox-
ford, 1991, Chapter 1.
3) For reviews: a) Koga K., Yuki Gosei Kagaku Kyokai Shi, 48, 463—475
(1990); b) Cox P. S., Simpkins N. S., Tetrahedron: Asymmetry, 2, 1—
26 (1991); c) Waldmann H., Nachr. Chem. Tech. Lab., 39, 413—418
(1991); d) Koga K., Pure Appl. Chem., 66, 1487—1492 (1994); e)
Koga K., Shindo M., Yuki Gosei Kagaku Kyokai Shi, 53, 1021—1032
(1995); f ) Simpkins N. S., Pure Appl. Chem., 68, 691—694 (1996); g)
Idem, “Advanced Asymmetric Synthesis,” ed. by Stephenson G. R.,
Chapman & Hall, London, 1996, pp. 111—125; h) O’Brien P., J.
Chem. Soc., Perkin Trans. 1, 1998. 1439—1457.
4) Corey E. J., Gross A. W., Tetrahedron Lett., 25, 495—498 (1984).
5) a) Shirai R., Tanaka M., Koga K., J. Am. Chem. Soc., 108, 543—546
(1986); b) Sato D., Kawasaki H., Shimada I., Arata Y., Okamura K.,
Date T., Koga K., ibid., 114, 761—763 (1992); c) Aoki K., Noguchi
H., Tomioka K., Koga K., Tetrahedron Lett., 34, 5105—5108 (1993);
d) Sugasawa K., Shindo M., Noguchi H., Tomioka K., Koga K., ibid.,
37, 7377—7380 (1996); e) Yamashita T., Sato D., Kiyoto T., Kumar,
A., Koga K., ibid., 37, 8195—8198 (1966); f ) Toriyama M., Sugasawa
K., Shindo M., Tokutake N., Koga K., ibid., 38, 567—570 (1997); g)
Aoki K., Koga K., ibid., 38, 2505—2506 (1997); h) Shirai R., Sato D.,
Aoki K., Tanaka M., Kawasaki H., Koga K., Tetrahedron, 53, 5963—
5972 (1997); i) Sato D., Kawasaki H., Shimada I., Arata Y., Okamura
K., Date T., Koga K., ibid, 53, 7191—7200 (1997); j) Sato D.,
Kawasaki H., Koga K., Chem. Pharm. Bull., 45, 1399—1402 (1997);
k) Chatani H., Nakajima M., Kawasaki H., Koga K., Heterocycles, 46,
53—56 (1997); l) Aoki K., Tomioka K., Noguchi H., Koga K., Tetra-
hedron, 53, 13641—13656 (1997); m) Yamashita T., Sato D., Kiyoto
T., Kumar A., Koga K., ibid, 53, 16987—16998 (1997).
6) Hass H. B., Bender M. L., “Organic Syntheses,” Coo. Vol. IV, ed. by
Rabjohn N., John Wiley & Sons, Inc., New York, 1963, pp. 932—934.
7) A solution of methyl ester (1.16 g, 6 mmol) of (R)-31 in AcOEt (10 ml)
and a solution of (S)-10-camphorsulfonic acid (1.38 g, 6 mmol) in
AcOEt (70 ml) were mixed and the whole was heated to reflux for
10 min. The solvent was evaporated in vacuo, and the residue was re-
crystallized twice from AcOEt–ether to give the salt (monohydrate) as
colorless prisms (2.16 g, 85%). Anal. Calcd for C21H33NO7S: C, 56.87;
H, 7.50; N, 3.16. Found: C, 56.68; H, 7.41; N, 3.19. X-ray analysis
confirmed the absolute configuration. Crystal data: monoclinic, P21; a,
12.809 Å; b, 7.917 Å; c, 11.807 Å; Z density 2. R-factor, 0.0696.
8) Shirai R., Aoki K., Sato D., Kim H.-D., Murakata M., Yasukata T.,
Koga K., Chem. Pharm. Bull., 42, 690—693 (1994).
9) a) Kawai M., Matsuura T., Butsugan Y., Egusa S., Shishido M., Iman-
ishi Y., Bull. Chem. Soc. Jpn., 58, 3047—3048 (1985); b) Williams R.,
Hendrix J. A., J. Org. Chem., 55, 3723—3728 (1990); c) Inaba T.,
Kozono I., Fujita M., Ogura K., Bull. Chem. Soc. Jpn., 65, 2359—
2365 (1992).
10) Shioiri T., Yokoyama Y., Kasai Y., Yamada S., Tetrahedron, 32,
2211—2217 (1976).
References and Notes
1) Part XXXII: Aoki K., Koga K., Chem. Pharm. Bull., 48, 571—574