Synthesis of aminocyclohexitol via carbon-carbon bond-forming radical cyclization of oxime ether.

Article abstract of DOI:10.1248/cpb.51.100

The stannyl radical mediated-cyclization of oxime ether, derived from D-glucose, gave the aminocyclohexitol derivative. Stereoselective C-C bond forming cyclization proceeded via favorable conformers minimizing A(1,3)-strain between the oxime ether group and alpha-substituents.

Full text of DOI:10.1248/cpb.51.100

100
Notes
Chem. Pharm. Bull. 51(1) 100—103 (2003)
Vol. 51, No. 1
Synthesis of Aminocyclohexitol via Carbon–Carbon Bond-Forming
Radical Cyclization of Oxime Ether
Hideto MIYABE,1) Akiyoshi NISHIKI, and Takeaki NAITO*
Kobe Pharmaceutical University; Motoyamakita, Higashinada, Kobe 658–8558, Japan.
Received October 3, 2002; accepted November 7, 2002; published online November 11, 2002
The stannyl radical mediated-cyclization of oxime ether, derived from D-glucose, gave the aminocyclohexitol
derivative. Stereoselective C–C bond forming cyclization proceeded via favorable conformers minimizing A1,3-
strain between the oxime ether group and a-substituents.
Key words radical reaction; oxime ether; cyclization
The aminocyclitols such as mannostatin, trehazolin, and treated with O-benzylhydroxyamine hydrochloride in pyri-
allosamindin are well known to be powerful inhibitors of gly- dine to give oxime ether 15 in 91% yield, as an E/Z mixture
cosidases.2) Recently, our group and Marco-Contelles/Chi- in a 9 : 2 ratio. Treatment of 15 with 2,2-dimethoxypropane
aira’s group have independently reported the investigations in the presence of p-TsOH gave the acetonide 16 in 94%
into the radical cyclization of oxime ethers as a useful yield. Deprotection of methoxyphenylmethyl (MPM) group
method for preparing various types of five-membered of 16 by treatment with DDQ followed by mild oxidation of
aminocyclitols.3—8) In contrast, the synthesis of six-mem- the resulting alcohol 17 with chromium(VI) oxide-pyridine
bered aminocyclitols has not been widely studied; thus, the afforded the aldehyde 6 as an E/Z mixture. In the recent stud-
synthesis of aminocyclohexitols based on the radical cycliza- ies on the radical reaction of oxime ether, we have observed
tion of oxime ethers derived from saccharides has been a no remarkable effect of the geometry of the starting oxime
subject of current interest due to their therapeutic applica- ether group on either the chemical yield or stereoselectivity
tions.9)
by employing geometrically pure E- and Z-isomer.15) Thus,
Marco-Contelles/Chiaira’s group reported the SmI2-medi- oxime ether 6 was subjected to the following radical reac-
ated radical cyclization of oxime ether 1 giving the aminocy- tions, without the separation of E/Z-isomers.
clohexitols 2 and 3 with low selectivity (Chart 1).3,4) In our
We next examined the stannyl radical-promoted cycliza-
recent studies on the radical reaction of oxime ether 4, we tion of oxime ether 6. Treatment of an E/Z mixture of 6 with
found that A1,3-strain effect between the oxime ether group tributyltin hydride in the presence of AIBN in boiling ben-
and a-substituents is important for stereocontrol of the ben- zene gave a 3 : 1 mixture of two cyclized products trans-7
zyloxyamino group on product 5 (Chart 2).10) In this paper, and cis-7 in 81% combined yield in favor of trans-7. As ex-
we report that the radical cyclization of oxime ether 6 pro- pected, the configuration of the benzyloxyamino group on
ceeded with an excellent selectivity concerning the stereo- product 7 was highly controlled in the radical cyclization of 6
chemistry of the benzyloxyamino group on product 7 via fa- as a result of A1,3-strain effect around oxime ether group
vorable conformers minimizing A1,3-strain around the oxime (Fig. 1). The preferential formation of the trans-7 could be
ether group.
Results and Discussion
Oxime ether 6 was prepared as shown in Chart 3. Accord-
ing to the literature,11) the commercially available 1,2,3,4,6-
pentaacetyl-D-glucose 8 was treated with p-TolSH in the
presence of BF3·OEt2 to give 9. Deacetylation of 9 followed
by selective protection of 4,6-hydroxyl groups using p-
anisaldehyde dimethylacetal gave 10 in 96% yield.12) Benzy-
lation of 10 using benzyl bromide and NaH followed by
treatment with NaBH3CN in the presence of trifluoroacetic
acid (TFA) gave alcohol 12.13) Treatment of 12 with N-io-
dosuccinimide (NIS) in the presence of AcOH gave the ac-
etate 13 in 98% yield.14) Subsequent deacetylation of 13 af-
Chart 1
forded the hemiacetal 14 in 96% yield, which was then
Chart 2
∗ To whom correspondence should be addressed. e-mail: taknaito@kobepharma-u.ac.jp
© 2003 Pharmaceutical Society of Japan

January 2003
101
Chart 3
Fig. 1. Stereochemical Feature, X-Ray Crystal Structure of trans-7 and NOE Correlations of trans-7 and cis-7
Chart 4
explained by less steric and electronic repulsions of the ketyl benzyloxyamino group of trans-7 with LiAlH4 followed by
radical moiety and the oxime ether group. The rationale of N-acylation of the resulting crude amine with (Boc)2O af-
the reaction pathway of this 6-exo-trig radical cyclization is forded the N-Boc derivative 18 in 48% yield and the oxazoli-
that the stannyl radical initially reacted with the oxygen atom done 19 in 42% yield. The N-Boc derivative 18 could be con-
of the formyl group to form the ketyl radical which attacked verted into the oxazolidone 19 in 61% yield by treatment
intramolecularly the oxime ether group to give the cyclized with NaH in THF. The aminocyclohexitol derivative 20 was
products.
We were able to separate and purify isomers of trans-7 and
prepared by treatment of 19 with Dowex 50W-X8 in MeOH.
In conclusion, we have shown an A1,3-strain effect on the
cis-7 by the medium-pressure column chromatography. The stannyl radical mediated-cyclization of oxime ether derived
configuration of the major product trans-7 was determined from D-glucose for preparing the aminocyclohexitol deriva-
by X-ray analysis. The stereostructure of the minor product tive.
1
cis-7 was deduced from comparison of the H-NMR spec-
trum with that of the major product trans-7 and from nuclear
Overhanser effect (NOE) correlations.
The major product trans-7 was converted into the
spectively. Preparative TLC separations were carried out on precoated silica
aminocyclohexitol derivative 20 (Chart 4). Reduction of the gel plates (E. Merck 60F254). Medium-pressure column chromatography was
Experimental
General Melting points are uncorrected. 1H- and 13C-NMR spectra
were recorded at 500, 300, and 200 MHz and at 125, 75, and 50 MHz, re-

102
Vol. 51, No. 1
performed using Lobar größe B (E. Merck 310-25, Lichroprep Si60). Flash
under a nitrogen atmosphere at 20 °C. After being stirred at the same tem-
column chromatography was performed using E. Merck Kieselgel 60 (230— perature for 10 min, 12 (1.0 g, 1.70 mmol) was added to the reaction mixture
400 mesh).
at 20 °C. After being stirred at the same temperature for 30 min, the reaction
mixture was diluted with saturated sodium thiosulfate and CH2Cl2. The or-
ganic phase was washed with saturated NaHCO3, water, and saturated NaCl,
dried over MgSO4, and concentrated at reduced pressure. Purification by
flash column chromatography (AcOEt/hexane 1 : 2) afforded 13 (870 mg,
4-Methylphenyl (S)-4,6-O-[(4-Methoxyphenyl)methylene]-1-thio-b-D-
glucopyranoside (10) To a solution of 911) (50.0 g, 0.11 mol) in MeOH
(600 ml) was added NaOMe (28% in MeOH, 2.57 ml) under a nitrogen at-
mosphere at 20 °C. After being stirred at the same temperature for 1 h,
Dowex 50W-X8 was added to the reaction mixture. The reaction mixture 98%) as a colorless oil (a mixture of a/b-isomer). 1H-NMR of major isomer
was filtered and the filtrate was concentrated at reduced pressure to afford (CDCl3) d: 2.15 (3H, s), 2.56 (1H, d, Jꢁ2.5 Hz), 3.60—3.84 (6H, m), 3.80
the alcohol. To a solution of the resulting alcohol in MeCN (350 ml) were
(3H, s), 4.46, 4.51 (2H, ABq, Jꢁ12 Hz), 4.62, 4.69 (2H, ABq, Jꢁ11.5 Hz),
4.75, 4.96 (2H, ABq, Jꢁ11.5 Hz), 6.34 (1H, d, Jꢁ3.5 Hz), 6.85—7.36 (14H,
added p-anisaldehyde dimethylacetal (37.5 ml, 0.22 mol) and p-TsOH (1.4 g,
7.26 mol) under a nitrogen atmosphere at 20 °C. After being stirred at the m). IR (CHCl3) cmꢀ1: 3554, 1752. HR-MS (EI) m/z: 522.2233 (Calcd for
same temperature for 20 h, Et3N (1.0 ml, 7.26 mmol) was added to the reac-
tion mixture. After the reaction mixture was concentrated at reduced pres-
C30H34O8 (Mꢂ): 522.2254).
6-O-[(4-Methoxyphenyl)methyl]-2,3-bis-O-(phenylmethyl)-D-glucopy-
sure, the resulting residue was diluted with AcOEt and then the organic ranose (14) To a solution of 13 (2.9 g, 5.57 mmol) in MeOH (30 ml) was
phase was washed with 3% HCl, water, saturated NaHCO3, water, and satu- added NaOMe (28% in MeOH, 0.12 ml) under a nitrogen atmosphere at
rated NaCl. The extract was dried over MgSO4 and concentrated at reduced
20 °C. After being stirred at the same temperature for 11 h, Dowex 50W-X8
was added to the reaction mixture. The reaction mixture was filtered and the
pressure. Purification by recrystallization (hexane/AcOEt 3 : 1) afforded 10
(42.8 g, 96%) as colorless crystals. mp 152—157 °C. [a]D25 ꢀ36.1° (cꢁ1.00, filtrate was concentrated at reduced pressure. Purification by recrystalliza-
1
CHCl3). H-NMR (CDCl3) d: 2.36 (3H, s), 2.68 (1H, br s), 2.83 (1H, br s),
3.39—3.55 (3H, m), 3.70—3.90 (2H, m), 4.35 (1H, dd, Jꢁ10, 3.5 Hz), 3.79
(3H, s), 4.56 (1H, d, Jꢁ9.5 Hz), 5.48 (1H, s), 6.86—7.45 (8H, m). 13C-NMR
(CDCl3) d: 21.0, 55.1, 68.3, 70.2, 72.4, 74.3, 80.0, 88.5, 101.6, 113.6, 127.5,
tion (AcOEt) afforded 14 (2.6 g, 96%) as colorless crystals (a mixture of
1
a/b-isomer). mp 111—114 °C. H-NMR of major isomer (CDCl3) d: 2.41
(1H, d, Jꢁ2.5 Hz), 2.99 (1H, d, Jꢁ2.5 Hz), 3.52—3.64 (4H, m), 3.78 (1H, t,
Jꢁ9 Hz), 3.79 (3H, s), 3.98 (1H, dt, Jꢁ9.5, 4 Hz), 4.46, 4.51 (2H, ABq,
129.3, 129.7, 133.3, 138.4, 160.1. Some carbon peaks were missing due to Jꢁ11.5 Hz), 4.69, 4.75 (2H, ABq, Jꢁ12Hz), 4.76, 4.97 (2H, ABq,
their overlapping. IR (CHCl3) cmꢀ1: 3592. High resolution (HR)-MS (elec-
Jꢁ11.5 Hz), 5.22 (1H, t, Jꢁ3 Hz), 6.84—7.37 (14H, m). IR (CHCl3) cmꢀ1
:
tron impact (EI)) m/z: 404.1289 (Calcd for C21H24O6S (Mꢂ): 404.1294). 3594. HR-MS (EI) m/z: 480.2158 (Calcd for C28H32O7 (Mꢂ): 480.2148).
Anal. Calcd for C21H24O6S·3/2H2O: C, 58.45; H, 6.31. Found: C, 58.34; H, Anal. Calcd for C28H32O7: C, 69.98; H, 6.71. Found: C, 69.94; H, 6.71.
6.05.
4-Methylphenyl (S)-4,6-O-[(4-Methoxyphenyl)methylene]-2,3-bis-O- O-(Phenylmethyl)oxime (15) To a solution of 14 (24 mg, 0.05 mmol) in
(phenylmethyl)-1-thio-b-D-glucopyranoside (11) To suspension of pyridine (0.3 ml) was added O-benzylhydroxylamine hydrochloride (8 mg,
6-O-[(4-Methoxyphenyl)methyl]-2,3-bis-O-(phenylmethyl)-D-glucose
a
NaH (60% in mineral oil, 7.7 g, 0.19 mol) in DMF (50 ml) was added 10
(32.0 g, 76.5 mol) under a nitrogen atmosphere at 0 °C. After being stirred at
the same temperature for 30 min, benzyl bromide (20.2 ml, 0.17 mol) was
added to the reaction mixture at 20 °C. After being stirred at the same tem-
perature for 20 h, the reaction mixture was diluted with Et2O and then the or-
0.05 mmol) under a nitrogen atmosphere at 20 °C. After being stirred at the
same temperature for 20 h, the reaction mixture was diluted with AcOEt and
then the organic phase was washed with 3% HCl, water, saturated NaHCO3,
water, and saturated NaCl. The extract was dried over MgSO4 and concen-
trated at reduced pressure. Purification by preparative TLC (AcOEt/hexane
ganic phase was washed with water, saturated NaHCO3, water, and saturated 1 : 1) afforded 15 (26.6 mg, 91%) as a colorless oil (E : Zꢁ9 : 2). 1H-NMR of
NaCl. The extract was dried over MgSO4 and concentrated at reduced pres-
sure. Purification by recrystallization (hexane) afforded 11 (34.2 g, 76%) as
colorless crystals. mp 135—136 °C. [a]D24 ꢀ32.1° (cꢁ1.03, CHCl3). 1H-
E-isomer (CDCl3) d: 2.40 (1H, d, Jꢁ5 Hz), 2.50 (1H, d, Jꢁ9 Hz), 3.50—
3.74 (4H, m), 3.79 (3H, s), 4.00 (1H, dd, Jꢁ7, 1.5 Hz), 4.28 (1H, dd, Jꢁ8.5,
7 Hz), 4.40, 4.58 (2H, ABq, Jꢁ12 Hz), 4.45, 4.47 (2H, ABq, Jꢁ11 Hz),
NMR (CDCl3) d: 2.34 (3H, s), 3.43 (1H, ddd, Jꢁ10, 9, 5 Hz), 3.47 (1H, dd, 4.60, 4.80 (2H, ABq, Jꢁ11 Hz), 5.12 (2H, s), 6.85—7.37 (19H, m), 7.49
Jꢁ9.5, 9 Hz), 3.66 (1H, t, Jꢁ9 Hz), 3.78 (1H, t, Jꢁ10 Hz), 3.79 (3H, s),
(1H, d, Jꢁ8.5 Hz). IR (CHCl3) cmꢀ1: 3561. HR-MS (EI) m/z: 585.2723
3.81 (1H, t, Jꢁ9 Hz), 4.35 (1H, dd, Jꢁ10, 5 Hz), 4.68 (1H, d, Jꢁ9.5 Hz), (Calcd for C35H39NO7 (Mꢂ): 585.2727).
4.76, 4.92 (2H, ABq, Jꢁ11 Hz), 4.81, 4.86 (2H, ABq, Jꢁ11 Hz), 5.54 (1H,
s), 6.89—7.44 (18H, m). 13C-NMR (CDCl3) d: 20.9, 55.1, 68.4, 70.0, 75.0,
75.6, 80.2, 81.2, 82.8, 88.3, 100.9, 113.4, 127.1, 127.5, 127.6, 127.9, 128.0,
6-O-[(4-Methoxyphenyl)methyl]-4,5-O-(1-methylethylidene)-2,3-bis-
O-(phenylmethyl)-D-glucose O-(Phenylmethyl)oxime (16) To a solution
of 15 (5.4 g, 9.20 mmol) in 2,2-dimethoxypropane (50 ml) was added p-
128.2, 129.0, 129.6, 132.8, 137.9, 138.1, 159.8. Some carbon peaks were TsOH (65 mg, 0.34 mmol) under a nitrogen atmosphere at 20 °C. After being
missing due to their overlapping. HR-MS (EI) m/z: 584.2249 (Calcd for stirred at the same temperature for 20 h, Et3N (0.05 ml, 0.36 mmol) was
C35H36O6S (Mꢂ): 584.2233). Anal. Calcd for C35H36O6S: C, 71.89; H, 6.26. added to the reaction mixture, and then the reaction mixture was concen-
Found: C, 71.90; H, 6.21. trated at reduced pressure. The residue was diluted with AcOEt and then the
4-Methylphenyl (S)-6-O-[(4-Methoxyphenyl)methyl]-2,3-bis-O- organic phase was washed with 3% HCl, water, saturated NaHCO3, water,
(phenylmethyl)-1-thio-b-D-glucopyranoside (12) To a solution of 11
(10 g, 17.1 mmol), NaBH3CN (5.4 g, 85.5 mmol), and 4A MS (3.0 g) in
DMF (30 ml) was added a solution of TFA (13.2 ml, 0.17 mol) in DMF
(30 ml) under a nitrogen atmosphere at 20 °C. After being stirred at the same
and saturated NaCl. The extract was dried over MgSO4 and concentrated at
reduced pressure. Purification by flash column chromatography (AcOEt/
hexane 1 : 2) afforded 16 (5.4 g, 94%) as a colorless oil (E : Zꢁ5 : 1). 1H-
NMR of E-isomer (CDCl3) d: 1.33 (3H, s), 1.42 (3H, s), 3.42 (2H, d,
temperature for 20 h, acetone (5 ml) and Et3N (23.8 ml, 0.17 mmol) were Jꢁ6 Hz), 3.58 (1H, t, Jꢁ4.5 Hz), 3.76 (3H, s), 4.06 (1H, q, Jꢁ6 Hz), 4.23—
added to the reaction mixture at 0 °C. The reaction mixture was diluted with 4.67 (8H, m), 5.09 (2H, s), 6.79—7.36 (19H, m), 7.56 (1H, d, Jꢁ7.5 Hz).
Et2O and then the organic phase was washed with 3% HCl, water, saturated HR-MS (EI) m/z: 625.3026 (Calcd for C38H43NO7 (Mꢂ): 625.3040).
NaHCO3, water, and saturated NaCl. The extract was dried over MgSO4 and
concentrated at reduced pressure. Purification by flash column chromatogra-
4,5-O-(1-Methylethylidene)-2,3-bis-O-(phenylmethyl)-D-glucose
(Phenylmethyl)oxime (17) To a solution of 16 (488 mg, 0.78 mmol) in
O-
phy (AcOEt/hexane 1 : 2) afforded 12 (9.4 g, 94%) as colorless crystals. mp
CH2Cl2 (7.9 ml) and H2O (0.5 ml) was added DDQ (267 mg, 1.17 mmol)
66—67 °C (Hexane). [a]D27 ꢀ8.81° (cꢁ1.11, CHCl3). H-NMR (CDCl3) d: under a nitrogen atmosphere at 20 °C. After being stirred at the same tem-
2.31 (3H, s), 2.60 (1H, br d, Jꢁ2 Hz), 3.43 (1H, br t, Jꢁ10 Hz), 3.44 (1H, dd, perature for 1 h, the reaction mixture was diluted with CH2Cl2 and then the
Jꢁ10, 9 Hz), 3.52 (1H, t, Jꢁ9 Hz), 3.63 (1H, br dt, Jꢁ9, 2 Hz), 3.70—3.77 organic phase was washed with water and saturated NaCl. The extract was
(2H, m), 3.81 (3H, s), 4.48, 4.50 (2H, ABq, Jꢁ11.5 Hz), 4.61 (1H, d, dried over MgSO4 and concentrated at reduced pressure. Purification by
1
Jꢁ10 Hz), 4.73, 4.91(2H, ABq, Jꢁ10.5 Hz), 4.78, 4.89 (2H, ABq, flash column chromatography (AcOEt/hexane 1 : 2) afforded 17 (377 mg,
1
Jꢁ11.5 Hz), 6.87—7.46 (18H, m). 13C-NMR (CDCl3) d: 20.9, 55.0, 69.9,
71.6, 73.1, 75.1, 75.2, 77.9, 80.2, 85.0, 87.7, 113.6, 127.6, 127.7, 128.1,
128.2, 128.4, 129.2, 129.4, 129.5, 129.6, 129.8, 132.4, 137.5, 137.9, 138.3,
159.1. IR (CHCl3) cmꢀ1: 3586. HR-MS (EI) m/z: 586.2370 (Calcd for
C35H38O6S (Mꢂ): 586.2389). Anal. Calcd for C35H38O6S: C, 71.65; H, 6.53.
Found: C, 71.48; H, 6.51.
96%) as a colorless oil (E : Zꢁ4 : 1). H-NMR of E-isomer (CDCl3) d: 1.33
(3H, s), 1.46 (3H, s), 2.26 (1H, br s), 3.53 (2H, br m), 3.67 (1H, br t,
Jꢁ5 Hz), 3.92 (1H, br q, Jꢁ6 Hz), 4.22 (1H, dd, Jꢁ8, 5 Hz), 4.30, 4.59 (2H,
ABq, Jꢁ12 Hz), 4.47 (1H, t, Jꢁ6 Hz), 4.59, 4.69 (2H, ABq, Jꢁ11 Hz), 5.11
(2H, s), 7.21—7.37 (15H, m), 7.57 (1H, d, Jꢁ8 Hz). IR (CHCl3) cmꢀ1
3497. HR-MS (EI) m/z: 505.2465 (Calcd for C30H35NO6 (Mꢂ): 505.2464).
:
6-O-[(4-Methoxyphenyl)methyl]-2,3-bis-O-(phenylmethyl)-D-glucopy-
ranose-1-acetate (13) To a suspension of NIS (383 mg, 1.70 mmol) in
Et2O (8.5 ml) and CH2ClCH2Cl (8.5 ml) was added AcOH (9.8 ml, 0.17 mol)
4,5-O-(1-Methylethylidene)-2,3-bis-O-(phenylmethyl)-D-gluco-hexodi-
aldose 1-[O-(Phenylmethyl)oxime] (6) To a solution of pyridine (3.1 ml,
38.8 mmol) in CH2Cl2 (31 ml) was portionwise added CrO3 (1.9 g, 19.4

January 2003
103
mmol) under a nitrogen atmosphere at 20 °C. After being stirred at the same
54.3, 69.6, 73.3, 74.0, 75.8, 78.5, 80.0, 82.6, 96.8, 109.8, 127.6, 127.9,
temperature for 15 min, a solution of 17 (982 mg, 1.94 mmol) in CH2Cl2 128.2, 128.2, 128.4, 137.9, 138.1, 156.8. Some carbon peaks were missing
(7.8 ml) was added to the reaction mixture. After the reaction mixture was due to their overlapping. IR (CHCl3) cmꢀ1: 3691, 1707. HR-MS (EI) m/z:
stirred at the same temperature for 30 min, the solvent was evaporated at re- 500.2657 (Calcd for C28H38NO7 (MꢂHꢂ): 500.2648). Anal. Calcd for
duced pressure. After the resulting residue was diluted with Et2O and filtered
through a pad of Celite, the filtrate was concentrated at reduced pressure.
Purification by flash column chromatography (AcOEt/hexane 1 : 2) afforded
6 (937 mg, 96%) as a colorless oil (E : Zꢁ5 : 1). 1H-NMR of E-isomer
(CDCl3) d: 1.34 (3H, s), 1.55 (3H, s), 3.65 (1H, dd, Jꢁ7, 2 Hz), 4.13, 4.70 (3H, s), 1.55 (3H, s), 3.71 (1H, br dd, Jꢁ9, 1.5 Hz), 3.87 (1H, dd, Jꢁ3,
(2H, ABq, Jꢁ11 Hz), 4.25 (1H, dd, Jꢁ8, 2.5 Hz), 4.37, 4.59 (2H, ABq, 1.5 Hz), 4.01 (1H, ddd, Jꢁ12, 9, 1.5 Hz), 4.32 (1H, dd, Jꢁ12, 3 Hz), 4.40,
C28H37NO7: C, 67.31; H, 7.46; N, 2.80. Found: C, 67.02; H, 7.68; N, 2.77.
4-Deoxy-1,2-O-(1-methylethylidene)-4-(carboxyamino)-5,6-bis-O-
(phenylmethyl)-D-myo-inositol Intramol. 3,4-Ester (19) mp 157—
158 °C (Et2O). [a]D28 ꢀ9.3° (cꢁ0.55, CHCl3). 1H-NMR (CDCl3) d: 1.38
Jꢁ12 Hz), 4.39 (1H, dd, Jꢁ8, 7 Hz), 4.74 (1H, dd, Jꢁ8, 2 Hz), 5.12 (2H, s),
7.21—7.37 (15H, m), 7.61 (1H, d, Jꢁ8 Hz), 9.49 (1H, d, Jꢁ2.5 Hz). IR
4.65 (2H, ABq, Jꢁ12 Hz), 4.56, 4.60 (2H, ABq, Jꢁ11 Hz), 4.57 (1H, br dd,
Jꢁ7, 3 Hz), 4.69 (1H, dd, Jꢁ7, 3 Hz), 4.96 (1H, br s), 7.26—7.28 (10H, m).
(CHCl3) cmꢀ1: 1725. HR-MS (EI) m/z: 503.2290 (Calcd for C30H33NO6 13C-NMR (CDCl3) d: 23.9, 25.9, 54.0, 70.1, 71.8, 72.3, 75.6, 77.8, 80.1,
(Mꢂ): 503.2308).
82.7, 111.3, 127.7, 127.9, 128.2, 128.4, 128.5, 128.6, 136.9, 137.4, 159.4. IR
(CHCl3) cmꢀ1: 3438, 1769. HR-MS (CI) m/z: 425.1845 (Calcd for
C24H27NO6 (Mꢂ): 425.1838). Anal. Calcd for C24H27NO6: C, 67.75; H, 6.40;
N, 3.29. Found: C, 67.70; H, 6.50; N, 3.35.
Radical Reaction of Oxime Ether 6 To a boiling solution of 6
(937 mg, 1.86 mmol) in benzene (14 ml) was added portionwise (5 ml/h) a
solution of Bu3SnH (1.0 ml, 3.72 mmol) and AIBN (61 mg, 0.37 mmol) in
benzene (4.0 ml) under a nitrogen atmosphere. The reaction mixture was
4-Deoxy-4-(carboxyamino)-5,6-bis-O-(phenylmethyl)-D-myo-inositol,
heated at reflux for 1.5 h and then the solvent was evaporated at reduced Intramol. 3,4-Ester (20) To a solution of 19 (50 mg, 0.12 mmol) in
pressure. The resulting residue was diluted with MeCN and the MeCN phase MeOH/H2O (20 : 1, 5.2 ml) was added Dowex 50W-X8 (55 mg) under a ni-
was washed with hexane and concentrated at reduced pressure. Purification trogen atmosphere at 20 °C. After being refluxed for 24 h, the reaction mix-
by medium-pressure column chromatography (AcOEt/hexane 1 : 2) afforded ture was filtered and the filtrate was concentrated at reduced pressure. Purifi-
cis-7 (207 mg, 22%) as a colorless oil and trans-7 (522 mg, 59%) as color-
less crystals.
cation by preparative TLC (AcOEt/hexane 1 : 1) afforded 20 (39 mg, 87%)
as a colorless oil. [a]D28 ꢀ31.4° (cꢁ1.32, CHCl3). 1H-NMR (CDCl3) d: 3.15
5-Deoxy-1,2-O-(1-methylethylidene)-5-[(phenylmethoxy)amino]-3,4- (2H, br s), 3.44 (1H, br dd), 3.56—3.65 (2H, br m), 3.75 (1H, br d), 4.01
bis-O-(methylphenyl)-L-chiro-inositol (cis-7) [a]D27 ꢀ72.8° (cꢁ0.79, (1H, br dd), 4.34 (1H, br s), 4.62, 4.76 (2H, ABq, Jꢁ12 Hz), 4.79, 4.80 (2H,
CHCl3). 1H-NMR (CDCl3) d: 1.36 (3H, s), 1.44 (3H, s), 2.83 (1H, br s), 3.22 ABq, Jꢁ11 Hz), 5.59 (1H, br s), 7.25—7.33 (10H, m). J-Values of three pro-
(1H, dd, Jꢁ9.5, 2.5 Hz), 3.58 (1H, t, Jꢁ9.5 Hz), 3.66 (1H, dd, Jꢁ9.5, 7 Hz),
ton signals (d: 3.44, 3.75, 4.01) were not correctly calculated due to the
4.26—4.29 (2H, m), 4.31 (1H, dd, Jꢁ7, 6 Hz), 4.47, 4.92 (2H, ABq, broad spectrum. 13C-NMR (CDCl3) d: 55.0, 66.4, 73.3, 73.8, 75.7, 78.5,
Jꢁ11 Hz), 4.63, 4.67 (2H, ABq, Jꢁ12 Hz), 4.71, 4.88 (2H, ABq, Jꢁ11 Hz),
6.11 (1H, br s), 7.19—7.38 (15H, m). 13C-NMR (CDCl3) d: 25.9, 27.8, 61.5,
66.8, 73.4, 74.8, 74.9, 76.2, 76.3, 79.7, 84.4, 109.0, 127.4, 127.7, 127.8,
80.8, 84.0, 127.7, 127.8, 128.0, 128.4, 128.5, 137.8, 138.2, 160.6. Some car-
bon peaks were missing due to their overlapping. IR (CHCl3) cmꢀ1: 3562,
3429, 1773. HR-MS (EI) m/z: 385.1527 (Calcd for C21H23NO6 (Mꢂ):
127.9, 128.1 (2C), 128.3, 128.4, 128.6, 137.0, 138.0, 138.3. IR (CHCl3) 385.1525).
cmꢀ1: 3513. HR-MS (CI) m/z: 505.2465 (Calcd for C30H35NO6 (Mꢂ):
505.2464).
Acknowledgements We thank a Grant-in-Aid for Scientific Research
4-Deoxy-1,2-O-(1-methylethylidene)-4-[(phenylmethoxy)amino]-5,6- (B) from the Ministry of Education, Culture, Sports, Science and Technol-
bis-O-(phenylmethyl)-D-myo-inositol (trans-7) mp 112—114 °C
ogy of Japan and the Science Research Promotion Fund of the Japan Private
(Hexane). [a]D28 ꢀ71.2° (cꢁ2.14, CHCl3). 1H-NMR (CDCl3) d: 1.39 (3H, s), School Promotion Foundation for research grants. We also thank Dr. H. Hi-
1.47 (3H, s), 2.77 (1H, br d), 2.94 (1H, t, Jꢁ10 Hz), 3.63 (1H, t, Jꢁ10 Hz),
3.71 (1H, br dd, Jꢁ10, 6.5 Hz), 3.97 (1H, ddd, Jꢁ10, 4, 2 Hz), 4.18 (1H, dd,
ramatsu and Dr. K. Aoe, Tanabe Seiyaku, Co. Ltd., for X-ray analysis.
Jꢁ6.5, 5.5 Hz), 4.48 (1H, dd, Jꢁ5.5, 4 Hz), 4.62, 4.91 (2H, ABq, References and Notes
Jꢁ10.5 Hz), 4.68, 4.71 (2H, ABq, Jꢁ11 Hz), 4.72, 4.91 (2H, ABq,
Jꢁ12 Hz), 6.27 (1H, br s), 7.26—7.38 (15H, m). 13C-NMR (CDCl3) d: 26.0,
27.7, 62.4, 65.7, 73.4, 75.2, 75.5, 75.9, 79.4, 84.1, 109.9, 127.5, 127.7,
127.8, 128.0, 128.1, 128.2, 128.3, 128.4, 128.5, 137.2, 138.3. Some carbon
peaks were missing due to their overlapping. IR (CHCl3) cmꢀ1: 3536. HR-
MS (SIMS) m/z: 506.2548 (Calcd for C30H35NO6 (MꢂHꢂ): 506.2540).
Anal. Calcd for C30H35NO6: C, 71.27; H, 6.98; N, 2.77. Found: C, 71.26; H,
7.05; N, 2.77. Crystal data of trans-7: C30H35NO6, space group P212121 with
aꢁ18.845(2), bꢁ24.499(4), cꢁ5.879(4) Å, Vꢁ2714(1) Å, final R value
0.0684 for 2009 reflections.
Conversion of trans-7 to 18 and 19 To a solution of trans-7 (522 mg,
1.09 mmol) in THF (8.7 ml) was added LiAlH4 (249 mg, 6.55 mmol) under a
nitrogen atmosphere at 20 °C. After the reaction mixture was heated at reflux
for 1 h, the mixture was carefully diluted with Et2O and then excess of the
reagent was decomposed by addition of water. The organic phase was
washed with saturated NaCl, dried over MgSO4, and concentrated at reduced
pressure to afford the amine. To a solution of the resulting amine in MeCN
(20 ml) were added DMAP (122 mg, 1.09 mmol) and (Boc)2O (0.3 ml,
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(AcOEt/hexane 1 : 1) afforded 18 (263 mg, 48%) as colorless crystals and 19
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4-Deoxy-1,2-O-(1-methylethylidene)-4-[[(1,1-dimethylethoxy)car- 13) Johansson R., Samuelsson B., J. Chem. Soc., Chem. Commun., 1984,
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Jꢁ8.5 Hz), 3.74—3.84 (3H, m), 4.23 (1H, t, Jꢁ6 Hz), 4.43 (1H, dd, Jꢁ6, 15) Miyabe H., Torieda M., Inoue K., Tajiri K., Kiguchi T., Naito T., J.
3 Hz), 4.51 (1H, br s), 4.58, 4.83 (2H, ABq, Jꢁ12 Hz), 4.69, 4.84 (2H, ABq,
Org. Chem., 63, 4397—4407 (1998).
Jꢁ11 Hz), 7.26—7.38 (10H, m). 13C-NMR (CDCl3) d: 25.7, 27.5, 28.2,