Ring-selective synthesis of O-heterocycles from acyclic 3-O-allyl-monosaccharides via intramolecular nitrone-alkene cycloaddition

Article abstract of DOI:10.1016/S0040-4020(00)01138-8

Intramolecular 1,3-dipolar cycloadditions of nitrones formed from 3-O-allyl-D-glucose and D-altrose (both with threo-configuration at C-2,3) afford oxepanes selectively whereas the same reactions of nitrones derived from 3-O-allyl-D-allose and D-mannose (both with erythro-configuration at C-2,3) give tetrahydropyrans selectively.

Full text of DOI:10.1016/S0040-4020(00)01138-8

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 1573±1579
Ring-selective synthesis of O-heterocycles from acyclic
3-O-allyl-monosaccharides via intramolecular
nitrone±alkene cycloaddition
Tony K. M. Shingp and Yong-Li Zhong
Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong
Received 27 June 2000; revised 14 November 2000; accepted 30 November 2000
AbstractÐIntramolecular 1,3-dipolar cycloadditions of nitrones formed from 3-O-allyl-d-glucose and d-altrose (both with threo-
con®guration at C-2,3) afford oxepanes selectively whereas the same reactions of nitrones derived from 3-O-allyl-d-allose and d-mannose
(both with erythro-con®guration at C-2,3) give tetrahydropyrans selectively. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
idene-a-d-mannopyranoside (5)12 via sequential epoxide
opening with sodium allyl oxide and acidic hydrolysis in
55% overall yield) with N-methyl hydroxylamine in re¯ux-
ing aqueous ethanol followed by acetylation afforded exclu-
sively oxepane tetraacetate 4 or 10, respectively (Schemes 1
and 2). The constitution and stereochemistry of 4 and 10
were con®rmed by X-ray crystallographic analyses.11
Cyclic and polycyclic ethers occur widely in marine organ-
isms, especially in red algae and dino¯agellates.1 Breve-
toxin B2 and ciguatoxin3 are two examples of polycyclic
ether comprising of fused tetrahydropyran and oxepane
rings, and are selective activators of voltage-sensitive
sodium channels in nerves, heart, and muscle.4 We are inter-
ested in the use of intramolecular nitrone±alkene cycload-
dition5 (INAC) reactions for the construction of these
bioactive O-heterocycles. The INAC reactions of O-allyl-
nitrones derived from d-glucose to construct O-heterocycles
was ®rst reported by Collins,6 then by Bhattacharjya,7 and
by our research group.8 Actually, the application of INAC
reactions to sugar derivatives was ®rst described 28 years ago
by Tronchet9 to produce furanose isoxazolidines. Recently,
INAC reactions have gained popularity among synthetic
chemists and its applications in organic synthesis have ¯our-
ished.10 However, the stereochemical course of the INAC
reactions is not well understood. In this article, we report in
detail that the stereochemical outcome of the INAC reactions
of nitrones derived from 3-O-allyl-d-hexoses is dependent
only on the relative con®guration at C-2,3 and thus 3-O-
allyl-d-glucose and -d-altrose (both with threo-con®guration
at C-2,3) afford oxepanes selectively whereas 3-O-allyl-d-
allose and -d-mannose (both with erythro-con®guration at
C-2,3) give tetrahydropyrans (THPs) selectively. A prelimin-
ary account of this work was recently reported.11
Scheme 1. (i) MeNHOH.HCl, NaHCO3, 80% EtOH (aq), re¯ux, 48 h; (ii)
Ac2O, DMAP, pyridine, CH2Cl2, rt, 6 h, 53% overall from 1.
2. Results and discussion
Treatment of 3-O-allyl-d-glucose (1)7 or 3-O-allyl-d-altrose
(7) (obtainable from methyl 2,3-anhydro-4,6-O-benzyl-
Scheme 2. (i) CH2vCHCH2OH, Na, re¯ux, 90%; (ii) 30% HCl(aq), re¯ux,
24 h, 60%; (iii) MeNHOH.HCl, NaHCO3, 80% EtOH (aq), re¯ux, 48 h; (iv)
Ac2O, DMAP, pyridine CH2Cl2, rt, 6 h, 55% overall from 7.
p
Corresponding author. Tel.: 1852-2609 6344; fax: 1852-2603 5057;
e-mail: tonyshing@cuhk.edu.hk
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01138-8

1574
T. K. M. Shing, Y.-L. Zhong / Tetrahedron 57 (2001) 1573±1579
Scheme 4. (i) 30% HCl(aq), re¯ux, 24 , 66%; (ii) MeNHOH.HCl, NaHCO3,
80% EtOH(aq), re¯ux, 48 h; (iii) Ac2O, DMAP, pyridine, CH2Cl2, rt, 24 h,
8% overall from 17; (iv) Ac2O, DMAP, pyridine, CH2Cl2, rt, 24 h, 37%
overall from 17.
Scheme 3. (i) 30% HCl(aq), re¯ux, 24 h, 70%; (ii) MeNHOH.HCl,
NaHCO3 80% EtOH(aq), re¯ux, 48 h; (iii) Ac2O, DMAP, pyridine,
CH2Cl2, rt, 24 h, 8% overall from 10; (iv) Ac2O, DMAP, pyridine,
CH2Cl2, rt, 24 h, 33% overall from 10.
On the other hand, the similar reaction of 3-O-allyl-d-allose
(12) (obtainable from acidic hydrolysis of diacetonide 1113)
or 3-O-allyl-d-mannose (19) (from acidic hydrolysis of
acetal 1814) with N-methyl hydroxylamine gave THP tetra-
acetates 15 and 17or 22 and 24, respectively (Schemes 3 and
4). The ring size (by COSY and HMQC) and the stereo-
chemistry (by J and NOESY) of the cycloadducts 15, 17,
and 24 were assigned by NMR spectroscopic techniques and
those of 22 were corroborated by an X-ray11 crystallo-
graphic analysis.
The above results may be rationalized as follows. Re-
subjection of the respective cycloadducts 3, 9, 14, 16, 21,
and 23 to the INAC reaction conditions for 56 h did not
cause any change and the cycloadducts were recovered
essentially in quantitative yields, thus hinting at a kinetically
controlled reaction. The molecular mechanics calculations
according to the MM2 force ®eld of Allinger15 showed that
the Esteric of the pyranoisoxazolidine (e.g. 14) is roughly 8±
10 kcal mol21 more stable than the corresponding oxepano-
isoxazolidine. On the basis of the above ®ndings and since
Figure 1.

T. K. M. Shing, Y.-L. Zhong / Tetrahedron 57 (2001) 1573±1579
1575
Figure 3.
and hence free from 1,3-diaxial interactions) were ener-
getically more favorable than the transition-states that
led to the corresponding oxepanes (Fig. 1). In addition,
these transition-states 13a and 13b; 20a and 20b may
also be stabilized by a vinylogous anomeric effect17
(sC±OH!ppCvN stabilization). Examination with molecular
models indicates that orbital overlap for cycloaddition
appears to be more effective via Z-nitrone-S-cis-allyl ether
transition-states 13b and 20b than via E-nitrone-S-trans-
allyl ethers 13b and 20a, respectively. On the other hand,
a similar chair-like transition-state for the INAC reaction of
1 would incur 1,3-diaxial interactions in either conformation
2a or 2b and the respective THP cycloadduct 25 or 26 was
not observed (Fig. 2). No vinylogous anomeric effect is
expected in 2a or 2b because there is no ef®cient orbital
overlap between the HO±C s bond and the CvN p bond.
The alternative transition-state 2c that led to oxepane 3 is
energetically more favorable in this case. The exclusive
formation of oxepanoisoxazolidine 9 from 3-O-allyl-d-
altrose (7) can be rationalized in a similar manner.
Figure 2.
Z- and E-nitrones are known to interconvert under the reac-
tion conditions,16 it is reasonable to assume that the product
selectivity of the INAC reactions was dependent only on the
respective transition-state energies.
We propose that the INAC reactions generally prefer to
proceed through chair-like transition-state conformations
that afford THPs. The observation that the THPs 14, 16,
21 and 23 were formed exclusively led to the conclusion
that the transition-states 13a and 13b; 20a and 20b (with
substituents at C-2,3 occupying pseudoequatorial positions
Scheme 5. (i) MeOCOCl, TEA, CH2Cl2; (ii) 90% aq. TFA; (iii) NalO4, dioxane±water; (iv) NaBH4, MeOH±H2Ov, MeOH, NaOMe; (iv) acetone, CSA, (vii)
BnBr, NaH, THF; (viii) 90% aq. TFA; (ix) NalO4, dioxane±water; AcOH, CH2Cl2; (x) MeNHOH.HCl, NaHCO3, 80% aq. EtOH.

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T. K. M. Shing, Y.-L. Zhong / Tetrahedron 57 (2001) 1573±1579
3. Conclusion
4.2. General procedure B for INAC reactions
Since the chirality at C-4,5 is the same in all the four 3-O-
allyl-d-hexoses 1, 7, 12, and 19, the observed stereoselectivity
should only be dependent on the relative stereochemistry at
C-2,3. We conclude that nitrones derived from 3-O-allyl
sugars having threo-con®guration at C-2,3 would give
oxepanoisoxazolidines whereas those having erythro-con®g-
uration at C-2,3 would afford pyranoisoxazolidines predomi-
nantly, and the ring selectivity is independent of the
substituent R (see Fig. 3).
Sodium hydrogen carbonate (218 mg, 2.6 mmol) was added
to a solution of the 3-O-allyl-pyranose (220 mg, 1.0 mmol)
and N-methyl hydroxylamine hydrochloride (217 mg,
2.6 mmol) in 80% aqueous EtOH (10 mL) and the resultant
mixture was heated under re¯ux for 48 h. The cooled
solution was concentrated to give a yellow syrup that was
immediately used in the next stage without puri®cation.
Acetic anhydride (0.6 mL, 6 mmol), pyridine (1 mL,
12 mmol), DMAP (cat.) and CH2Cl2 (5 mL) were added to
the syrup. After being stirred for 6 h, the mixture was evapo-
rated to dryness and the residue was chromatographed on
silica gel to give the cycloadduct peracetate.
This conclusion is supported by the observation that 3-
O-allyl-2,4-di-O-benzyl-aldehydo-l-erythrose (27) (with
erythro-con®guration at C-2,3) on reaction with N-methyl
hydroxylamine gave exclusively pyran cycloadduct 29 in
88% yield (Scheme 5). This example also provides evidence
that hydrogen bonding may not have signi®cant effect on the
stereoselectivity of the INAC reactions. The aldehyde 27
was prepared in nine steps from 3-O-allyl-1,2-O-isopropyl-
idene-a-d-allofuranose (30)8 by standard transformations as
shown in Scheme 5.
4.3. General procedure C for INAC reactions
Sodium hydrogen carbonate (218 mg, 2.6 mmol) was added
to a solution of the aldehyde (1.0 mmol) and N-methyl hy-
droxylamine hydrochloride (217 mg, 2.6 mmol) in CH3CN
(10 mL) and the resultant mixture was heated under re¯ux
for 7 h. The reaction mixture was ®ltered and the ®ltrate was
extracted with CHCl3 (3£15 mL). The combined extracts
were washed with saturated aqueous NH4Cl (20 mL),
dried (MgSO4) and ®ltered. The ®ltrate was concentrated
to a yellow syrup that was chromatographed on silica gel
to give the cycloadduct.
The yields of the INAC reactions involving unprotected
sugar derivatives are moderate and the remaining materials
from the reactions are degradation products. The problem
of decomposition could be alleviated, by masking the
hydroxy groups as benzyl ethers. The INAC reactions of the
corresponding benzyl protected sugar derivatives are under
active investigation and will be reported in due course.
4.3.1. [1S-[1a,4a(1Rp,2Rp),5a,6a]]-1-(5-Acetyloxy-7-methyl-
3,8-dioxa-7-azabicyclo[4.2.1]non-4-yl)-1,2,3-propanetriol
triacetate (4). INAC reaction of 3-O-allyl-d-glucose (1)7
according to procedure B followed by ¯ash chromatography
[EtOAc±hexane (3:1)] afforded oxepane 4 in 53% yield as
colorless prisms: mp 1458C; Rf 0.33 [EtOAc±hexane (3:1)];
4. Experimental
[a]25 ˆ195.5 (c 1.0, CHCl3); IR (neat) 1744, 1372, 1224,
D
Melting points were measured in 8C and uncorrected. IR
spectra were recorded on an FT-IR spectrophotometer as
neat ®lms on KBr plates. Optical rotations were obtained
at 589 nm. 1H NMR spectra were measured at either 250 or
500 MHz. 13C NMR spectra were obtained at 62.9 MHz. 2D
NMR spectra were measured at 500 MHz. Elemental
analyses were performed at either the Shanghai Institute
of Organic Chemistry, The Chinese Academy of Sciences,
China, or the MEDAC Ltd., Department of Chemistry,
Brunel University, UK. Mass spectra were obtained using
EI or FAB techniques. All reactions were monitored by
analytical TLC performed on Merck aluminum precoated
plates of silical gel 60 F254 with detection by spraying with
5% w/v dodecamolybdophosphoric acid in ethanol and
subsequent heating. All columns were packed wet using
E. Merck silica gel 60 (230±400 mesh) as the stationary
phase and eluted using the ¯ash chromatographic technique.
THF was distilled from sodium benzophenone ketyl under a
nitrogen atmosphere.
1023 cm21; 1H NMR (CDCl3) d 2.02 (3H, s), 2.12 (6H, s),
2.20 (3H, s), 2.28±2.45 (1H, m), 2.55 (1H, d, Jˆ12.5 Hz),
2.67 (3H, s), 3.45±3.52 (2H, m), 3.63 (1H, dd, Jˆ7.4,
1.0 Hz), 4.04 (1H, d, Jˆ7.4 Hz), 4.22 (2H, dq, Jˆ11.9,
5.0 Hz), 4.60 (1H, dd, Jˆ7.5, 2.8 Hz), 5.03±5.10 (2H, m),
5.38 (1H, dd, Jˆ7.5, 3.8 Hz); 13C NMR (CDCl3) d 20.6
(2C), 20.9 (2C), 27.1, 46.5, 61.1, 65.3, 69.4, 71.9, 72.4,
73.2, 74.7, 78.6, 169.7, 169.9, 170.4, 170.6; EIMS m/z (rela-
tive intensity) 417 (M1, 2), 43 (CH3CO1, 100). Anal. Calcd
for C18H27NO10: C, 51.79; H, 6.52; N, 3.36. Found: C,
51.69; H, 6.56; N, 3.33.
4.3.2. Methyl 3-O-Allyl-4,6-O-benzylidene-a-d-altro-
pyranoside (6). Sodium metal (250 mg, 10.9 mmol) was
added to allyl alcohol (5 ml) at 08C very slowly and
the resulting mixture was stirred for 0.5 h. Methyl 2,3-
anhydro-4,6-O-benzylidene-a-d-mannopyranoside (5)12
(168 mg, 0.64 mmol) was added to the mixture, which
then was heated under re¯ux for 6 h. The reaction mixture
was cooled to room temperature and saturated NH4Cl
(5 mL) was added. The mixture was extracted with CHCl3
(3£30 mL). The combined extracts were washed with satu-
rated aqueous NH4Cl (20 mL), dried with MgSO4 and
®ltered. The ®ltrate was concentrated to a yellow syrup
and chromatographed on silica gel to give allyl ether 6
(187 mg, 90%) as pale yellow crystals: mp 748C; Rf 0.46
4.1. General procedure A for the preparation of
3-O-allyl-pyranose by acidic hydrolysis
A solution of the acetal protected sugar derivative
(2.0 mmol) in 30% aqueous HCl (5 mL) was heated under
re¯ux for 24 h. The reaction mixture was cooled and the
solvent was removed in vacuo. The residue was chromato-
graphed on silica gel to give the 3-O-allyl-pyranose.
[Et2O±hexane (1:1)]; [a]25 ˆ167.9 (c 0.9, CHCl3); IR
D
(neat) 3450, 1650, 1460, 1380, 1138, 1044, 1017 cm21
;

T. K. M. Shing, Y.-L. Zhong / Tetrahedron 57 (2001) 1573±1579
1577
1H NMR (CDCl3) d 2.01 (1H, d, Jˆ5.8 Hz), 3.42 (3H, s),
3.71±3.81 (1H, m), 3.88 (1H, t, Jˆ2.9 Hz), 3.96±4.01
(2H, m), 4.21 (1H, ddt, Jˆ13.5, 6.1, 1.3 Hz), 4.28±4.37
(3H, m), 4.59 (1H, s), 5.17 (1H, dq, Jˆ10.5, 1.3 Hz), 5.29
(1H, dq, Jˆ19.0, 1.3 Hz), 5.55 (1H, s), 5.87±5.96 (1H,
m), 7.30±7.50 (5H, m); 13C NMR (CDCl3) d 55.6, 58.5,
69.3, 70.2, 72.4, 74.8, 77.0, 101.9, 102.2, 116.9, 126.1
(2C), 128.2 (2C), 129.0, 135.0, 137.6; EIMS m/z (relative
intensity) 322 (M1, 0.3), 41 (CH2vCHCH21, 100). Anal.
Cacld for C17H22O6: C, 63.34; H, 6.88. Found: C, 63.26; H,
6.72.
Jˆ12.4, 7.5 Hz, H-8a), 4.46 (1H, dd, Jˆ12.4, 2.4 Hz, H-8b),
5.11 (1H, dd, Jˆ10.3, 3.9 Hz, H-4ax), 5.19 (1H, ddd, Jˆ7.5,
4.6, 2.4 Hz, H-7), 5.37 (1H, dd, Jˆ4.6, 3.2 Hz, H-6); 13C
NMR (CDCl3) d 20.7 (4C), 45.1, 47.2, 62.4, 66.3, 66.4,
66.7, 69.4, 70.2, 70.6, 73.4, 169.8 (4C); EIMS m/z (relative
intensity) 417 (M1, 13), 43 (CH3CO1, 100). Anal. Cacld for
C18H27NO10: C, 51.79; H, 6.52; N, 3.36. Found: C, 52.11; H,
6.71; N, 3.02.
For 17: Rf 0.30 [EtOAc±hexane (3:1)]; [a]25 ˆ111.3 (c
D
1
1.0, CHCl3); IR (neat) 1744, 1372, 1225, 1045 cm21; H
NMR (CDCl3) d 2.04 (3H, s), 2.10 (6H, s), 2.16 (3H, s),
2.63 (3H, s, N±CH3), 2.98±3.08 (2H, m), 3.53 (1H, dd,
Jˆ8.4, 3.9 Hz, H-5ax), 3.65 (1H, t, Jˆ7.5 Hz, H-9a), 3.71
(1H, dd, Jˆ12.5, 3.0 Hz, H-1ax), 3.95 (1H, d, Jˆ12.5 Hz,
H-1eq), 4.17 (1H, dd, Jˆ7.5, 5.0 Hz, H-9b), 4.19 (1H, dd,
Jˆ12.0, 6.0 Hz, H-8a), 4.36 (1H, dd, Jˆ12.0, 2.0 Hz, H-8b),
4.94 (1H, dd, Jˆ8.4, 7.5 Hz, H-4ax), 5.31 (1H, d, Jˆ3.9 Hz,
H-6), 5.36 (1H, dt, Jˆ6.0, 2.0 Hz, H-7); 13C NMR (CDCl3)
d 20.4, 20.6 (2C), 20.8, 40.0, 43.5, 62.0, 64.5, 67.1, 67.9,
68.2, 69.5, 70.0, 77.5, 169.3, 169.4, 169.6, 170.4; EIMS m/z
(relative intensity) 417 (M1, 2.3), 43 (CH3CO1, 100). Anal.
Cacld for C18H27NO10: C, 51.79; H, 6.52; N, 3.36. Found: C,
51.70; H, 6.68; N, 3.23.
4.3.3. 3-O-Allyl-d-altrose (7). Acidic hydrolysis of
compound 6 according to procedure A followed by ¯ash
chromatography [MeOH±CHCl3 (1:3)] afforded hemiacetal
5 in 60% yield as a pale yellow syrup: Rf 0.37 [MeOH±
CHCl3 (1:3)]. 3-O-Allyl-d-altrose (5) was immediately used
in the next step.
4.3.4. [1R-[1a,4a(1Rp,2Rp),5a,6a]]-1-(5-Acetyloxy-7-
methyl-3,8-dioxa-7-azabicyclo[4.2.1]non-4-yl)-1,2,3-
propanetriol triacetate (10). INAC reaction of 3-O-allyl-
d-altrose (7) according to procedure B followed by ¯ash
chromatography (EtOAc) afforded oxepane tetraacetate 10
in 55% yield as colorless prisms: mp 99±99.58C; Rf 0.34
(EtOAc); [a]25 ˆ229.9 (c 0.9, CHCl3); IR (neat) 1750,
4.3.7. 3-O-Allyl-d-mannose (19). Acidic hydrolysis of
methyl 3-O-allyl-4,6-O-benzylidene-a-d-mannopyranoside
(18)14 according to procedure A followed by ¯ash chroma-
tography [MeOH±CHCl3 (1:3)] afforded hemiacetal 19 in
66% yield as a sticky white solid: Rf 0.37 [MeOH±CHCl3
(1:3)]. The product was immediately used in the next step.
D
1
1390, 1220 cm21; H NMR (CDCl3) d 2.01 (3H, s), 2.08
(6H, s), 2.09 (3H, s), 2.35±2.45 (1H, m), 2.55 (1H, d,
Jˆ12.4 Hz), 2.67 (3H, s), 3.45 (1H, dd, Jˆ6.4, 4.9 Hz),
3.67 (2H, brs), 4.08±4.16 (2H, m), 4.38 (1H, dd, Jˆ12.0,
3.8 Hz), 4.63 (1H, bd, Jˆ8.1 Hz), 4.91 (1H, d, Jˆ4.6 Hz),
5.13 (1H, dd, Jˆ10.2, 2.0 Hz), 5.38 (1H, ddd, Jˆ10.2, 3.8,
2.1 Hz); 13NMR (CDCl3) d 20.7, 20.8, 20.9 (2C), 27.3, 46.5,
62.5, 65.5, 69.1, 70.0, 70.9, 72.6, 74.1, 79.0, 169.7, 170.1,
170.6 (2C); EIMS m/z (relative intensity) 417 (M1, 3), 43
(CH3CO1, 100). Anal. Cacld for C18H27NO10: C, 51.79; H,
6.52; N, 3.36. Found: C, 51.77; H, 6.54; N, 2.99.
4.3.8. [3aS-[3aa6b (1Rp,2Rp),7a,7ab]]-1-[7-(Acetyloxy)-
hexahydro-1-methyl-3H-pyrano[4,3-c]isoxazol-6-yl]-1,2,3-
propanetriol triacetate (22) and [3aR-[3aa,6b (1Rp,
2Rp),7a,7ab]]-1-[7-(acetyloxy)hexahydro-1-methyl-3H-
pyrano[4,3-c]isoxazol-6-yl]-1,2,3-propanetriol triacetate
(24). INAC reaction of 3-O-allyl-d-mannose (19) according
to procedure B followed by ¯ash chromatography [EtOAc±
hexane (3:1)] afforded 22 in 8% yield as colorless prisms
and 24 in 37% yield as a white solid.
4.3.5. 3-O-Allyl-d-allopyranose (12). Acidic hydrolysis of
3-O-allyl-1,2:5,6-di-O-isopropylidene-a-d-allofuranose (11)13
according to procedure A followed by ¯ash chromatography
[MeOH±CHCl3 (1:3)] afforded hemiacetal 12 in 70% yield
as a sticky white solid: Rf 0.33 [MeOH±CHCl3 (1:3)]. The
product was immediately used in the next step.
For 22: mp 95±968C; Rf 0.35 [EtOAc±hexane (3:1)];
[a]20 ˆ22.5 (c 0.4, CHCl3); IR (neat) 2967, 2933, 2887,
D
1
1745, 1367, 1229, 1039 cm21; H NMR?(CDCl3) d 2.05
4.3.6. [3aR-[3aa,6a(1Rp,2Rp),7b,7aa]]-1-[7-(Acetyloxy)-
hexahydro-1-methyl-3H-pyrano[4,3-c]isoxazol-6-yl]-1,2,3-
propanetriol triacetate (15) and [3aS-[3aa,6a(1Rp,2Rp),
7b,7aa]]-1-[7-(acetyloxy)hexahydro-1-methyl-3H-pyrano-
[4,3-c]isoxazol-6-yl]-1,2,3-propanetriol triacetate (17).
INAC reaction of 3-O-allyl-d-allose (12) according to
procedure B followed by ¯ash chromatography [EtOAc±
hexane (3:1)] afforded syrupy tetraacetates 15 and 17 in 8
and 33% yield, respectively.
(3H, s), 2.07 (3H, s), 2.10 (6H, s), 2.47 (1H, dd, Jˆ10.0,
9.5 Hz, H-3ax), 2.66 (3H, s, N±CH3), 2.73 (1H, m, H-2ax),
3.38 (1H, t, Jˆ11.0 Hz, H-1eq), 3.52 (1H, dd, Jˆ9.0,
2.0 Hz, H-5ax), 3.63 (1H, dd, Jˆ11.0, 6.8 Hz, H-1ax),
4.01 (1H, t, Jˆ7.7 Hz, H-9a), 4.12 (1H, dd, Jˆ12.5,
5.5 Hz, H-8a), 4.15 (1H, dd, Jˆ7.7, 5.0 Hz, H-9b), 4.41
(1H, dd, Jˆ12.5, 2.0 Hz, H-8b), 5.03 (1H, dd, Jˆ10.0,
9.0 Hz, H-4ax), 5.28±5.38 (2H, m); 13C NMR (CDCl3) d
21.3 (2C), 21.4, 21.7, 41.0, 47.1, 62.3, 65.2, 67.9, 69.4 (2C),
70.4, 79.1, 80.3, 166.5, 169.2, 170.1, 171.3; FABMS m/z
(relative intensity) [(M1H)1, 100]. Anal. Cacld for
C18H27NO10: C, 51.79; H, 6.52; N, 3.36. Found: C, 51.98;
H, 6.71; N, 3.22.
For 15: Rf 0.38 [EtOAc±hexane (3:1)]; [a]25 ˆ112.6 (c
D
1
1.2, CHCl3); IR (neat) 1744, 1400, 1225, 1045 cm21; H
NMR (CDCl3) d 2.01 (3H, s), 2.02 (3H, s), 2.07 (3H, s),
2.12 (3H, s), 2.67 (3H, s, N±CH3), 2.87±2.98 (1H, m, H-2),
3.27 (1H, dd, Jˆ5.1, 3.9 Hz, H-3), 3.50 (1H, d, Jˆ8.2 Hz,
H-9a), 3.57 (1H, t, Jˆ11.4 Hz, H-1eq), 3.95 (1H, dd,
Jˆ11.4, 7.0 Hz, H-1ax), 3.98 (1H, dd, Jˆ8.2, 5.0 Hz, H-
9b), 4.06 (1H, dd, Jˆ10.3, 3.2 Hz, H-5ax), 4.14 (1H, dd,
For 24: mp 82±838C; Rf 0.33 [EtOAc±hexane (3:1)];
[a]25 ˆ133.8 (c 1.0, CHCl3); IR (neat) 2950, 2850,
D
1
1747, 1371, 1227 cm21; H NMR (CDCl3) d 2.00 (6H, s),
2.06 (6H, s), 2.60 (3H, s, N±CH3), 3.07 (2H, m, H-2eq,

1578
T. K. M. Shing, Y.-L. Zhong / Tetrahedron 57 (2001) 1573±1579
H-3ax), 3.43 (1H, dd, Jˆ10.0, 2.0 Hz, H-5ax), 3.67 (1H, dd,
Jˆ13.0, 2.0 Hz, H-1ax), 3.76 (1H, t, Jˆ7.4 Hz, H-9a), 4.04
(1H, dd, Jˆ12.5, 6.5 Hz, H-8a), 4.08 (1H, d, Jˆ13.0 Hz,
H-1eq), 4.21 (1H, dd, Jˆ9.6, 7.4 Hz, H-9b), 4.36 (1H,
dd, Jˆ12.5, 2.5 Hz, H-8b), 4.86 (1H, dd, Jˆ10.0, 8.5 Hz,
H-4ax), 5.21 (1H, dd, Jˆ6.5, 2.0 Hz, H-6), 5.26 (1H, dq,
Jˆ6.5, 2.5 Hz, H-7); 13C NMR (CDCl3) d 21.1 (4C), 40.9,
44.6, 62.9, 66.3, 66.5, 68.0, 68.3, 69.8, 70.8, 76.8, 169.9,
170.2, 170.6, 171.0; EIMS m/z (relative intensity) 417 (M1,
85). Anal. Calcd for C18H27NO10: C, 51.79; H, 6.52; N, 3.36.
Found: C, 52.06; H, 6.74; N, 3.06.
13), 57 (C3H5O1, 57.5). Anal. Calcd for C9H14O6: C,
49.54; H, 6.47. Found: C, 49.15; H, 6.49.
4.3.13. 2-O-Allyl-d-ribitol (35). NaOMe (cat. amt.) was
added to a solution of 34 (1.1 g, 5.0 mmol) in MeOH
(25 mL) and stirred for 1 h. The mixture was concentrated
and the residue was chromatographed on silica gel to give
35 (0.96 g, 100%) as a sticky pale yellow solid:
[a]25 ˆ12.22 (c 0.9, MeOH); TLC [MeOH±CHCl3 (1:3)]
D
1
Rf 0.38; IR (neat) 3400, 2910, 1420, 1050 cm21; H NMR
(D2O) d 3.57±4.15 (7H, m); 4.13 (2H, dd, Jˆ1.4, 6.0 Hz);
5.25 (1H, dq, Jˆ10.3, 1.4 Hz); 5.33 (1H, dq, Jˆ17.2,
1.4 Hz); 5.97 (1H, ddt, Jˆ10.3, 17.2, 6.0 Hz); MS m/z 187
(5.4), 43 (C3H71, 100). Anal. Calcd for C8H16O5: C, 49.99;
H, 8.39. Found: C, 49.06; H, 8.11.
4.3.9. 3-O-Allyl-5,6-carbonate-1,2-O-isopropylidene-a-
d-allofuranose (31). Methyl chloroformate (0.7 mL,
9.1 mmol) was added to a solution of diol 308 (0.5 g,
1.92 mmol) and TEA (0.7 mL, 9.1 mmol) in CH2Cl2
(5 mL) at 08C. The reaction mixture was stirred for 3 h
and the solvent was removed in vacuo. Et2O (20 mL) was
added and the mixture was ®ltered. The solvent was
removed in vacuo and the residue was chromatographed
on silica gel to give carbonate 31 (0.53 g, 97%) as colorless
4.3.14. 2-O-Allyl-4,5-O-isopropylidene-d-ribitol (36).
Camphorsulfonic acid (cat. amt.) was added to a solution
of 35 (0.5 g, 2.6 mmol) in acetone (15 mL) and stirred for
1 h. NH3 solution (four drops) was added and the solvent
was removed in vacuo. The residue was chromatographed
on silica gel to give acetonide 36 (370 mg, 61%) as a pale
crystals: mp 728C; [a]27 ˆ81.7 (c 1.2, CHCl3); TLC [Et2O±
D
yellow syrup: [a]24 ˆ118.0 (c 1.4, CHCl3); TLC [EtOAc±
hexane (3:1)] Rf 0.32; IR (neat) 1801, 1168, 1085,
D
1
1021 cm21; H NMR (CDCl3) d 1.37 (3H, s); 1.59 (3H,
hexane (2:1)] Rf 0.33; IR (neat) 3450, 2950, 1400,
1
1066 cm21; H NMR (CDCl3) d 1.36 (3H, s); 1.43 (3H,
s); 3.77±3.81 (4H, m); 3.93±4.01 (1H, m); 4.19±4.28
(2H, m); 4.49 (2H, ddt, Jˆ2.2, 4.0, 6.9 Hz); 4.67 (1H, t,
Jˆ3.85 Hz); 4.92±5.00 (2H, m); 5.23±5.37 (2H, m); 5.77
(1H, d, Jˆ6.8 Hz); 5.84±6.00 (1H, m); MS m/z 271 (M1±
Me, 20.8), 43 (C3H71, 100). Anal. Cacld for C13H18O7: C,
54.54; H, 6.34. Found: C, 54.58; H, 6.18.
s); 3.52 (1H, q, Jˆ4.5 Hz); 3.73±4.24 (9H, m); 5.20±5.25
(1H, m); 5.26±5.34 (1H, m); 5.84±6.00 (1H, m); MS m/z
217 (M1±Me, 10), 43 (C3H71, 100). Anal. Calcd for
C11H20O5: C, 56.88; H, 8.68. Found: C, 56.06; H, 8.68.
4.3.15. 2-O-Allyl-1,3-di-O-benzyl-4,5-O-isopropylidene-
d-ribitol (37). Sixty percent sodium hydride (150 mg,
3.8 mmol) was washed with hexane (3£10 mL) and dry
THF (3 mL) was added. Diol 36 (255 mg, 1.1 mmol) and
benzyl bromide (0.4 mL, 3.3 mmol) in THF (3 mL) was
added slowly at 08C. TBAI (cat. amt.) was added and heated
to re¯ux for 3 h under nitrogen. Saturated aqueous NH4Cl
(10 mL) was added at 08C and the mixture was extracted
with CHCl3 (3£10 mL). The combined extracts were
washed with saturated aqueous NH4Cl (20 mL), dried
(MgSO4) and ®ltered. The ®ltrate was concentrated to a
yellow syrup and chromatographed on silica gel to give
benzyl ether 37 (383 mg, 84%) as pale yellow syrup:
4.3.10. 3-O-Allyl-5,6-carbonate-d-allofuranose (32). A
solution of the acetonide 31 (445 mg, 1.55 mmol) in 90%
TFA (3 mL) was stirred for 12 h. The acid was removed in
vacuo and the residue was chromatographed on silica gel to
give hemiacetal 32 (331 mg, 87%) as a colorless oil. TLC
[EtOAc±hexane (3:1)] Rf 0.34. The product was used imme-
diately in the next step.
4.3.11. 2-O-Allyl-4,5-carbonate-3O-formyl-d-ribose (33).
NaIO4 (4.6 g, 21 mmol) was added to a solution of 114
(1.2 g, 4.9 mmol) in 60% aqueous dioxane (70 mL). After
stirring for 4 h at rt, the reaction mixture was ®ltered and
concentrated to give 115 (0.95 g, 80%) as a yellow syrup.
The product was immediately used in the next stage without
further puri®cation.
[a]25 ˆ122.4 (c 1.2, CHCl3); TLC [Et2O±hexane (1:5)]
D
1
Rf 0.36; IR (neat) 2990, 2870, 1091, 1027 cm21; H NMR
(CDCl3) d 1.34 (3H, s); 1.41 (3H, s); 3.59±3.81 (4H, m);
3.89±4.27 (5H, m); 4.53 (2H, d, Jˆ1.9 Hz); 4.70 (2H, s);
5.16 (1H, dd, Jˆ1.5, 10.4 Hz); 5.30 (1H, dq, Jˆ17.2,
1.6 Hz); 5.83±5.99 (1H, m); 7.25±7.33 (10H, m); MS m/z
412 (M1, 0.1), 91 (C7H71, 100). Anal. Calcd for C25H32O5:
C, 72.79; H, 7.82. Found: C, 72.75; H, 7.82.
4.3.12. 2-O-Allyl-4,5-carbonate-d-ribitol (34). NaBH4
(140 mg, 3.8 mmol) in H2O (10 mL) was added to a solution
of 33 (0.95 g, 3.9 mmol) in MeOH (10 mL) at 08C. The
mixture was stirred for 6 h at rt and saturated aqueous
NH4Cl (20 mL) was added slowly. The mixture was
extracted with CH2Cl2 (3£40 mL). The combined extracts
were washed with saturated aqueous NH4Cl (20 mL), dried
(MgSO4) and ®ltered. The ®ltrate was concentrated to a
yellow syrup and chromatographed on silica gel to give
4.3.16. 2-O-Allyl-1,3-di-O-benzyl-d-ribitol (38). A solu-
tion of the acetonide 37 (260 mg, 0.64 mmol) in 90%
aqueous TFA (3 mL) was stirred for 3 h. The acid was
removed in vacuo and the residue was chromatographed
on silica gel to give diol 38 (171 mg, 72%) as colorless
diol 34 (0.76 g, 90%) as colorless oil: [a]27 ˆ119.3 (c
D
1.0, CHCl3); TLC [EtOAc±hexane (2:1)] Rf 0.31; IR
1
(neat) 3400, 1785, 1187, 1064 cm21; H NMR (CDCl3) d
oil: [a]25 ˆ119.8 (c 1.1, CHCl3); TLC [EtOAc±hexane
D
1
(3:2)]Rf 0.33; IR (neat) 3410, 2900, 1450, 1100 cm21; H
3.38±3.43 (1H, m); 3.65±3.89 (4H, m); 3.93±4.01 (1H, m);
4.10±4.24 (2H, m); 4.45 (1H, t, Jˆ8.4 Hz); 4.58 (1H, t,
Jˆ8.4 Hz); 4.93±5.00 (1H, m); 5.20±5.35 (2H, m); 5.85
(1H, ddt, Jˆ10.3, 17.2, 6.0 Hz); MS m/z 203 (M1±Me,
NMR (CDCl3) d 3.59±3.90 (6H, m); 4.01±4.24 (3H, m);
4.55 (2H, s); 4.61 (2H, d, Jˆ3.1 Hz); 5.16±5.31 (2H, m);
5.82±5.98 (1H, m); 7.26±7.34 (10H, m); MS m/z 253

T. K. M. Shing, Y.-L. Zhong / Tetrahedron 57 (2001) 1573±1579
1579
(M1±H2O, 2.2), 91 (C7H71, 100). Anal. Calcd for C22H28O5:
C, 70.95; H, 7.58. Found: C, 70.61; H, 7.56.
Murata, M.; Yasumoto, T.; Harada, N. Tetrahedron 1997,
53, 3057.
4. (a) Lewis, R. J.; Hoy, A. W.; McGif®n, D. C. Toxicon 1992,
30, 907. (b) Lewis, R. J.; Hoy, A. W.; Sellin, M. Toxicon 1993,
31, 1093. (c) Deshpande, S. S.; Alder, M.; Sheridan, R. E.
Toxicon 1993, 31, 459.
4.3.17.
3-O-Allyl-2,4-di-O-benzyl-aldehydo-l-threose
(27). NaIO4 (1.0 g, 4.7 mmol) was added to a solution of
the diol 38 (0.40 g, 1.07 mmol) in 60% aqueous dioxane
(15 mL) and stirred for 3 h at rt. The reaction mixture was
®ltered and concentrated to give aldehyde 27 as a pale
yellow syrup (0.3 g, 82%). The product was immediately
used in the next stage without further puri®cation.
5. For reviews, see: (a) Wade, P. A. Intramolecular 1,3-Dipolar
Cycloadditions, Trost, B. M., Fleming, I., Eds.; In Compre-
hensive Organic Synthesis; Pergamon: London, 1991; Vol. 4,
pp 1111. (b) Padwa, A.; Schoffstall, A. M. In Advances in
Cycloaddition; Curran, D. P., Ed.; JAI: Greenwich, 1990;
Vol. 2, pp 1. (c) Confalone, P. N.; Huie, E. M. Org. React.
1988, 36, 1.
4.3.18. [3aR-[3aa,6b,7a,7ab]]-7-Benzyloxy-6-(benzyloxy-
methyl)hexahydro-1-methyl-3H-pyrano[4,3-c]isoxazole
(29). INAC reaction of aldehyde 27 (0.3 g) according to
procedure C followed by ¯ash chromatography [EtOAc±
hexane (3:1)] afforded THP 29 (278 mg, 88%) as colorless
needles: mp 65±668C; Rf 0.32 [Et2O±hexane (3:1)];
6. Collins, P. M.; Ashwood, M. S.; Eder, H. Tetrahedron Lett.
1990, 31, 2055.
7. (a) Bhattacharjya, A.; Chattopadhyay, P.; Datta, D.;
Mukhopadhyay, R.; McPhail, D. R. J. Chem. Soc., Chem.
Commun. 1990, 1508. (b) Bhattacharjya, A.; Chattopadhyay,
P.; Mukhopadhyay, R. Tetrahedron Lett. 1993, 34, 3585.
8. (a) Shing, T. K. M.; Fung, W.-C.; Wong, C.-H. J. Chem. Soc.,
Chem. Commun. 1994, 449. (b) Shing, T. K. M.; Wong, C.-H.
Tetrahedron: Asymmetry 1994, 5, 1151. (c) Shing, T. K. M.;
Wong, C.-H.; Yip, T. Tetrahedron: Asymmetry 1996, 7, 1323.
9. Tronchet, J. M. J.; Mihaly, M. E. Helv. Chim. Acta. 1972, 55,
1266.
[a]24 ˆ216.1 (c 1.2, CHCl3); IR (neat) 2860, 1410,
D
1106, 1074 cm21; H NMR (CDCl3) d 2.65 (3H, s, N±
1
CH3), 3.04 (1H, m, H-2eq), 3.18 (1H, t, Jˆ7.3 Hz, H-
3ax), 3.36 (1H, ddd, Jˆ10.0, 5.5, 2.0 Hz, H-5ax), 3.46
(1H, dd, Jˆ10.0, 7.3 Hz, H-4ax), 3.60 (1H, dd, Jˆ10.8,
5.5 Hz, H-6a), 3.74 (1H, dd, Jˆ12.3, 3.3 Hz, H-1ax), 3.77
(1H, dd, Jˆ10.8, 2.0 Hz, H-6b), 3.79 (1H, dd, Jˆ9.0,
7.3 Hz, H-7a), 4.06 (1H, bd, Jˆ12.3 Hz, H-1eq), 4.24
(1H, dd, Jˆ9.9, 7.3 Hz, H-7b), 4.52 (1H, d, Jˆ11.2 Hz),
4.54 (1H, d, Jˆ12.2 Hz), 4.59 (1H, d, Jˆ12.2 Hz), 4.96
(1H, d, Jˆ11.2 Hz), 7.20±7.35 (10H, m); 13C NMR
(CDCl3) d 40.1, 43.7, 64.7, 67.8, 69.9, 70.7, 73.2, 73.6,
74.0, 78.6, 127.1(2C), 127.4 (4C), 128.0 (4C), 138.0,
138.6; EIMS m/z (relative intensity) 278 (M12C7H7, 13),
91 (C7H71, 100). Anal. Calcd for C22H27NO4: C, 71.52; H,
7.37; N, 3.79. Found: C, 71.27; H, 7.30; N, 3.51.
10. For recent reports, see: (a) Jung, M. E.; Vu, B. T. J. Org.
Chem. 1996, 61, 4427. (b) Broggini, G.; Folcio, F.; Sardone,
N.; Zecchi, G. Tetrahedron 1996, 52, 11849. (c) Gotoh, M.;
Mizui, T.; Sun, B.; Hirayama, K.; Noguchi, M. J. Chem. Soc.,
È
Perkin Trans. 1 1995, 1857. (d) Aurich, H. G.; Koster, H.
Tetrahedron 1995, 51, 6285. (e) Gottlieb, L.; Hassnor, A.
J. Org. Chem. 1995, 60, 3759. (f) Abiko, A.; Moriya, O.;
Filla, S. A.; Masamune, S. Angew. Chem. Int. Ed. Engl.
1995, 34, 793. (g) Kang, S. H.; Lee, H. S. Tetrahedron Lett.
1995, 36, 6713.
11. Shing, T. K. M.; Zhong, Y.-L.; Mak, T. C. W.; Wang, R.; Xue,
F. J. Org. Chem. 1998, 61, 8468.
Acknowledgements
12. Wiggins, L. F. Methods Carbohydr. Chem. 1963, 2, 188.
13. Bhattacharjee, A.; Chattopadhyay, P.; Kundu, A. P.; Mukho-
padhyay, R.; Bhattacharjya, A. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1996, 35B, 69.
This research was supported by the Hong Kong RGC
Earmarked Grant (Ref. No. CUHK457/95P).
14. (a) Partoni, J. J.; Stick, R. V.; Skelton, B. W.; White, A. H.
Aust. J. Chem. 1988, 41, 91. (b) Nashed, M. A. Carbohydr.
Res. 1978, 60, 200.
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