Synthesis of carbasugars from aldonolactones. Part II. 1 Preparation of polyhydroxy/aminocyclopentanes functionalised at all five ring carbons 2

Article abstract of DOI:10.1039/a907008g

Starting from (1R,5R,8R)-8-acetoxy-2-oxabicyclo[3.3.0]oct-6-en-3-one 4 the syntheses of 5-deoxy-4a(R)-hydroxy-4a-carba-α-D-ribo-hexofuranose 17, 5-deoxy-4a(R)-hydroxy-4a-carba-α-D-lyxo-hexofuranose 21, 5-deoxy-4a(R)-hydroxy-4a-carba-α-D-xylo-hexofuranose

Full text of DOI:10.1039/a907008g

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Synthesis of carbasugars from aldonolactones. Part II.1
Preparation of polyhydroxy/aminocyclopentanes functionalised
at all five ring carbons2
Steen K. Johansen and Inge Lundt*
Department of Organic Chemistry, Technical University of Denmark, Building 201,
DK-2800 Lyngby, Denmark. Fax: ϩ45 4593 3968; E-mail: okil@pop.dtu.dk
Received (in Cambridge, UK) 31st August 1999, Accepted 3rd November 1999
Starting from (1R,5R,8R)-8-acetoxy-2-oxabicyclo[3.3.0]oct-6-en-3-one 4 the syntheses of 5-deoxy-4a(R)-hydroxy-
4a-carba-α--ribo-hexofuranose 17, 5-deoxy-4a(R)-hydroxy-4a-carba-α--lyxo-hexofuranose 21, 5-deoxy-4a(R)-
hydroxy-4a-carba-α--xylo-hexofuranose 23 and 4a(R)-hydroxy-2-amino-2,5-dideoxy-4a(R)-hydroxy-4a-carba-α--
arabino-hexofuranose 1 have been achieved. The methodology included OsO4-catalysed dihydroxylation as well as
regioselective epoxide opening followed by calcium borohydride reduction of the lactone moiety.
Introduction
There is a considerable interest in the synthesis of highly func-
tionalised cyclopentanes bearing polyhydroxy as well as amino
substituents. One area where this class of compounds is of great
interest is as carbohydrate mimics. These polyhydroxycyclo-
pentanes or carbasugars3 can mimic furanoses as well as
pyranoses and the lack of the acetal function makes them
resistant to hydrolytic enzymes.
In particular, polyhydroxylated aminocyclopentanes have
been pursued by a number of groups, both for the synthesis of
carbocyclic nucleosides4 such as aristeromycin,5 carbovir6 and
the fully substituted epinor-BCA,7 as well as for the preparation
of glycosidase inhibitors8 like mannostatin A.9
Scheme 1 Reagents and conditions: (i) DBU, THF, reflux, 16 h; (ii)
HCl–MeOH, rt, 40 h; (iii) BzCl, pyridine, rt, 1.5 h; (iv) TBDPSCl,
imidazole, DCM, rt, 3.5 h.
We recently developed a short and efficient synthesis of
bicyclic cis-fused cyclopentane lactones like 214 (Scheme 1)
starting from bromodeoxyaldonolactones, which in themselves
are very useful synthons for a number of applications.15 These
bicyclic lactones have been converted into carbahexo- and
pentofuranoses functionalised at four of the five carbons in
the ring.1,14 We here report the functionalisation of the C-6
methylene group in 2, thereby giving access to cyclopentane
derivatives bearing functional groups at all five ring carbons. In
particular we have synthesised the novel polyhydroxyamino-
cyclopentane 1, which can be viewed as an analogue of the
above mentioned compounds. Furthermore the synthesis of
three novel polyhydroxycyclopentanes is also reported.
A number of polyhydroxylated aminocyclopentanes bearing
a methyl or hydroxymethyl group have been shown to be potent
glycosidase inhibitors. Allosamizoline10 is the aminocyclopenti-
tol moiety of the chitinase inhibitor allosamidin, trehazolin11 is
a trehalase inhibitor, and the two aminocyclopentanes I12 and
II13 are potent α-mannosidase and α--fucosidase inhibitors,
respectively. It has been postulated that the activity of these
compounds as glycosidase inhibitors arises from their ability to
act as transition-state analogues.13
Results and discussion
Having prepared a series of carbasugars1 we turned our
attention to finding methods for functionalising the remaining
J. Chem. Soc., Perkin Trans. 1, 1999, 3615–3622
This journal is © The Royal Society of Chemistry 1999
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carbon atom in the cyclopentane ring. Previously, we have
described the preparation of the trans-bromo acetate 3 from
the cis-diol 2 in good yield.1 Elimination of HBr from 3 would
introduce an allylic alcohol functionality, which in turn can
easily be further functionalised at both the double bond and in
the allylic position. The use of DBU as the base cleanly gave
the allylic acetate 4 in 83% yield (Scheme 1), while weaker
bases like Et3N and t-BuOK gave unsatisfactory results.
Deprotection then gave the allylic alcohol 5 in quantitative
yield.
For hydroxylation of the double bond we first investigated
the OsO4-catalysed dihydroxylation. Standard OsO4-catalysed
dihydroxylation conditions call for mixtures of acetone–water
or tert-butyl alcohol–water to be used as the solvent. However,
when 4 or 5 was dihydroxylated under these conditions, we
observed the formation of a third product besides the expected
endo and exo products. This compound, which complicates
separation by flash chromatography, arises from opening of
the lactone function in the endo product, followed by lactone
formation with the C-6 hydroxy group. The use of dry solvents
circumvented this problem with the necessary water for the
dihydroxylation supplied from N-methylmorpholine N-oxide
(NMO) monohydrate.
Scheme 3 Reagents and conditions: (i) OsO4, NMO, acetone, rt, 16 h;
(ii) Ac2O, pyridine, rt, 16 h.
Catalytic dihydroxylation of the allylic alcohol 5 using the
OsO4–NMO system gave a 3:1 ratio of exo to endo products
(Scheme 2 – entry a). This selectivity was reversed to 1:3 in
Scheme 4 Reagents and conditions: (i) TBHP, VO(acac)2, DCM,
reflux, 4 h; (ii) HClO4, H2O, rt, 40 h; (iii) NaN3, NH4Cl, DMF, 55 ЊC,
40 h; (iv) acetone, MgSO4, H2SO4, rt, 40 h.
Scheme 2 Reagents and conditions: (i) OsO4, NMO, acetone, rt, 16 h.
formed product 12 rapidly equilibrates under the reaction con-
ditions giving a racemic mixture of 12 and ent-12 as the isolated
product.
favour of the endo product with the allylic acetate 4 (entry b), so
we decided to investigate the influence of the size of the protect-
ing group in this dihydroxylation. The benzoate 6 (78%) and
tert-butyldiphenylsilyl (TBDPS) ether 7 (82%) (Scheme 1)
were synthesised and dihydroxylated to give 1:6 and greater
than 1:13 exo to endo ratios, respectively (Scheme 2 – entry c
and d). Thus, the selectivity of the dihydroxylation can be
controlled to a large degree by the size of the group in the
allylic position.
For practical applications the catalytic dihydroxylation of
compounds 4, 5 and 7 was found to be the most synthetically
useful (Scheme 3). From the allylic alcohol 5 the exo and endo
products (8 and 9) were isolated in 68 and 23% yield respect-
ively, whereas the allylic acetate 4 gave 19 and 59% yields of the
two products, respectively. Finally, dihydroxylation of TBDPS
ether 7 gave the endo product 10 (53%) as the only product
isolated.
We next investigated the epoxidation of the C-6/C-7 double
bond in 5, as the nucleophilic ring opening of epoxides usually
leads to formation of trans-products. Epoxidation using
MCPBA proceeded in very low yield and was non-selective,
whereas the vanadium catalysed epoxidation16 using tert-butyl
hydroxyperoxide (TBHP) and vanadyl acetylacetonate [VO-
(acac)2] exclusively gave the epoxide 11 in 81% yield (Scheme 4).
Opening of the epoxide 11 under aqueous acidic conditions
gave regioselective opening at C-6 resulting in a 50:1 mixture
of epimers from which the major product could be isolated
by recrystallisation in 71% yield. The isolated product did not
show an optical rotation, which is due to the compound being
a meso compound in non-lactonised form. Apparently the
The epoxide 11 was also used as a precurser for preparation
of the amino hydroxy motif, and opening of the epoxide with
various nitrogen nucleophiles was investigated. Treatment of
the epoxide 11 with liquid ammonia proceeded very slowly,
resulting in only 10% conversion after 12 days at 120 ЊC, and
the reaction was not deemed synthetically useful. For com-
parison full conversion was obtained after 5 days at 90 ЊC
when the epoxide was located in the 7,8-position.1 Previously,
we also had good results in opening of epoxides using
acetonitrile and boron trifluoride–diethyl ether in a Ritter-type
reaction to give trans-amino alcohols.1 Treatment of 11 under
these conditions gave however, a complex and inseparable mix-
ture of different amino alcohols. When sodium azide was used
as the nucleophile a 6:1 mixture of two regioisomeric azides
was obtained, inseparable by flash chromatography. Derivatis-
ation of the minor isomer as the acetonide allowed their separ-
ation by flash chromatography giving the protected C-6 azide
13 (6%) and the C-7 azide 14 (34% after recrystallisation)
(Scheme 4). Compared with the aforementioned 7,8-epoxide,1
the epoxide 11 reacts more slowly and less stereoselectively,
which can only be attributed to the lack of a neighbouring
lactone moiety.
The lactone moieties of the bicyclic systems were now
reduced in order to obtain carbahexofuranoses. Simple sodium
borohydride reduction is not possible due to the lack of an
electron-withdrawing substituent at C-4 and although lithium
aluminium hydride and borane are standard reagents for such
conversions, we prefer the use of calcium borohydride. This
3616
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reagent, which can easily be prepared in situ from calcium chlor-
ide and sodium borohydride1,17 and is commercially available,
nicely spans the gap between sodium borohydride and lithium
aluminium hydride. It is capable of working in protic solvents
like ethanol or methanol and still retains the activity to reduce
non-activated lactones.
Compound 8 was deacetylated to give the triol 15 (93%)
followed by calcium borohydride reduction and acetylation
(to ease purification) to give the pentaacetate 16 in 84% yield.
Deprotection gave 5-deoxy-4a(R)-hydroxy-4a-carba-α--ribo-
hexofuranose 17 in 80% yield (Scheme 5).
Scheme 6 Reagents and conditions: (i) Pd/C, H2, EtOH or MeOH,
HCl, rt, 16 h; (ii) CaCl2, NaBH4, EtOH, Ϫ20 ЊC to rt, 16 h; (iii)
Ca(BH4)2ؒ2THF, THF, Ϫ20 ЊC, 16 h; (iv) Ac2O, pyridine, rt, 16 h;
(v) HCl–MeOH, rt, 40 h; (vi) 4 M HCl, reflux, 4 h.
24 followed by acetylation and chromatography gave a 12:1
mixture of the aminocyclopentane 25 and the corresponding
bicyclic amine 26† and recrystallisation provided pure 25 in low
yield (28%). To add insult to injury, it turned out that deacetyl-
ation of 25 proved to be more difficult than expected. In order
to ensure complete deprotection rather harsh conditions (1 M
HCl; reflux; 4 h) had to be employed and this led to isomeris-
ation of the product. Milder reaction conditions (1 M HCl;
70 ЊC; 16 h, or NaOMe–MeOH; rt; 2 h) did not give N-
deacetylation as the literature might suggest.18
A different approach was thus needed and we decided to
return to the azide 14. If reduction of the lactone moiety could
be achieved without concomitant reduction of the azide group,
lactam formation should be avoided. As an added bonus this
would not give N-acetylation if acetylation were needed for
purification purposes. Our first attempt at reduction of the lac-
tone moiety using Ca(BH4)2ؒ2THF complex in ethanol–THF
gave formation of the desired azide 28 as well as the fully
reduced aminocyclopentane 1. When using THF as the only
solvent, the reduction followed by acetylation proceeded to give
the protected azidocyclopentane 27 as the only product in 47%
yield. This was then deacetylated to give the azide 28 (100%),
which could also be obtained directly from compound 14
(44%). Finally, catalytic hydrogenation of 28 gave 2-amino-2,5-
Scheme 5 Reagents and conditions: (i) HCl–MeOH, rt, 40 h; (ii) CaCl2,
NaBH4, EtOH, Ϫ20 ЊC to rt, 16 h; (iii) Ac2O, HClO4, rt, 1.5 h.
When compound 9 was deacetylated a 3:1 mixture of two
trihydroxy lactones tentatively assigned as 18 and 19 was
obtained in quantitative yield. Recrystallisation gave pure 18
(46%) which, as expected, equilibrated back to a 3:1 mixture of
18 and 19 upon dissolution in water. Likewise a 3:1 mixture of
18 and 19 was obtained from compound 10 (59%) after depro-
tection (not shown). The mixture of 18 and 19 was reduced and
acetylated to give 20 (71%), which after deprotection gave
dideoxy-4a(R)-hydroxy-4a-carba-α--arabino-hexofuranose
1
isolated as the hydrochloride in 95% yield.
In summary, four fully substituted hydroxy/aminocyclo-
pentane derivatives have been synthesised from the easily avail-
able allylic acetate 3. The compounds, which can be viewed as
sugar mimics, are 5-deoxy-4a(R)-hydroxy-4a-carba-α--ribo-
hexofuranose 17, 5-deoxy-4a(R)-hydroxy-4a-carba-α--lyxo-
hexofuranose 21, 5-deoxy-4a(R)-hydroxy-4a-carba-α--xylo-
hexofuranose 23 together with 2-amino-2,5-dideoxy-4a(R)-
hydroxy-4a-carba-α--arabino-hexofuranose 1. The compounds
presented here are both interesting in their own right as possible
glycosidase inhibitors but can also be used as building blocks
for synthesis of mimics of more complex natural products such
as nucleoside or saccharide analogues.
5-deoxy-4a(R)-hydroxy-4a-carba-α--lyxo-hexofuranose
21
(100%). In a similar manner 5-deoxy-4a(R)-hydroxy-4a-carba-
α--xylo-hexofuranose 23 was obtained from racemic com-
pound 12 following reduction–acetylation to the pentaacetate
22 (83%) and deprotection (80%).
Catalytic hydrogenation of the azide 14 gave the amino lac-
tone 24 as a hygroscopic oil in quantitative yield (Scheme 6). We
have previously with success used Ca(BH4)2 for the reduction of
amino lactones similar to 14,1 but in this case we could not
avoid lactam formation under the reaction conditions and the
subsequent reduction of the amide functionality. Reduction of
† Although we did not isolate this by-product, it is expected to have the
shown structure 26. For additional information see ref. 1.
J. Chem. Soc., Perkin Trans. 1, 1999, 3615–3622
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(5 ml) at 0 ЊC was added benzoyl chloride (0.45 ml, 3.87 mmol)
Experimental
and the mixture was stirred at rt for 1.5 h. Water (0.5 ml) was
added and the mixture was stirred for 0.5 h, followed by further
addition of water (40 ml) and extraction with dichloromethane
(4 × 25 ml). The combined organic phases were washed succes-
sively with water (20 ml), 1 M HCl (20 ml) and sat. aq. NaHCO3
(20 ml), dried (MgSO4) and concentrated to give a crude crys-
talline product (659 mg, 95%), which was recrystallised from
EtOAc–hexane to give the title compound 6 as colourless crys-
tals (541 mg, 78%), mp 121–124 ЊC. Further recrystallisation
(EtOAc–hexane) gave mp 125–126 ЊC; [α]D Ϫ321.6 (c 1.00,
CHCl3) (Found: C, 68.9; H, 5.0. Calc. for C14H12O4: C, 68.85;
H, 4.95%); δH(500 MHz; benzene-d6) 1.68 (1 H, dd, J4Ј,5 2.5, J4,4Ј
18.0, HЈ-4), 1.88 (1 H, dd, J4,5 10.5, J4,4Ј 18.0, H-4), 2.70 (1 H, m,
H-5), 4.45 (1 H, br d, J1,5 6.0, H-1), 5.12 (1 H, dd, J 2.0, J6,7 5.5,
H-6 or -7), 5.55 (1 H, dt, J 2.5, J6,7 5.5, H-7 or -6), 5.81 (1 H,
d, J 2.5, H-8), 7.01–7.05 (2 H, m, ArH), 7.10 (1 H, m, ArH),
8.03–8.05 (2 H, m, ArH); δC(62.5 MHz; CDCl3) 32.2 (C-4), 43.7
(C-5), 82.6 and 85.4 (C-1 ϩ -8), 128.3 (Ar-CH), 128.9 (C-6 or
-7), 129.4 (Ar-CH), 129.5 (Ar-C), 133.2 (Ar-CH), 139.0 (C-7 or
-6), 165.5 (ArCO), 175.2 (C-3).
THF was distilled from sodium/benzophenone, and dichloro-
methane from calcium hydride under nitrogen. Acetone was
dried over MgSO4. Mps were measured on a Heidolph oil bath
apparatus and are uncorrected. Specific rotations were meas-
ured on a Perkin-Elmer 241 polarimeter and the concentrations
are given in g 100 mlϪ1. [α]D-Values are given in units of 10Ϫ1
deg cm2 gϪ1. NMR spectra were recorded on Bruker AM 500
and AC 250 spectrometers. Chemical shifts (δ) were measured
in ppm and coupling constants (J) in Hz. For NMR spectra in
deuterated solvents, the solvent peak was used as reference
1
1
[CDCl3: δ 7.27 for H, δC 76.93 for 13C; D2O: δ 4.63 for H,
dioxane (δC 66.5) as internal reference for 13C; benzene-d6:
1
1
δ 7.16 for H, MeOH-d4: δ 3.31 for H, δC 49.0 for 13C]. When
necessary, NMR data were assigned using HH- and CH-
correlated spectra. Elemental analyses were performed by the
Institute of Physical Chemistry, University of Vienna and the
Department of Chemistry, University of Copenhagen. HRMS
(FAB) was performed by the Department of Chemistry,
University of Copenhagen. TLC was performed on Merck 60
F254 precoated silica plates and spots were detected by spraying
with a solution of 1.5% (NH4)6Mo7O24ؒ4H2O 1% Ce(SO4)ؒ
4H2O in 10% H2SO4 followed by charring. Flash chrom-
atography was performed with silica gel 60 (Grace AB Amicon,
35–70 µm). Concentrations were performed on a rotary evap-
orator at a temperature below 40 ЊC. Ca(BH4)2ؒ2THF was
purchased from Fluka Chemie AG.
(1R,5R,8R)-8-(tert-Butyldiphenylsilyloxy)-2-oxabicyclo[3.3.0]-
oct-6-en-3-one 7
To a solution of compound 5 (225 mg, 1.61 mmol) in dichloro-
methane (10 ml) were added imidazole (134 mg, 1.97 mmol) and
tert-butyl(chloro)diphenylsilane (0.49 ml, 1.92 mmol) and the
solution was stirred at rt for 3.5 h. The reaction mixture was
diluted with dichloromethane (40 ml) and washed with 1 M
HCl (2 × 10 ml) followed by re-extraction of the aqueous
phases with dichloromethane (20 ml). The combined organic
phases were washed with sat. aq. NaHCO3 (20 ml), dried
(MgSO4) and concentrated to give a crude product (quant.).
Purification by flash chromatography (EtOAc–hexane 25:75)
gave the title compound 7 as a colourless oil (500 mg, 82%), [α]D
Ϫ104.0 (c 1.05, CHCl3); δH(500 MHz; benzene-d6) 1.14 [9 H, s,
C(CH3)3], 1.64 (1 H, dd, J4Ј,5 2.5, J4,4Ј 18.0, HЈ-4), 1.85 (1 H, dd,
J4,5 10.0, J4,4Ј 18.0, H-4), 2.77 (1 H, m, H-5), 4.51 (1 H, br d, J1,5
6.0, H-1), 4.89 (1 H, br s, H-8), 5.01 (1 H, dd, J 2.0, J6,7 5.5, H-6
or -7), 5.33 (1 H, dt, J 2.5, J6,7 5.5, H-7 or -6), 7.18–7.25 (6 H, m,
ArH), 7.68–7.75 (4 H, m, ArH); δC(62.5 MHz; CDCl3) 18.8
[C(CH3)3], 26.5 [C(CH3)3], 32.0 (C-4), 43.1 (C-5), 81.5 (C-8),
88.1 (C-1), 127.4, 127.5, 129.5 and 129.6 (Ar-CH), 132.0 (C-6
or -7), 132.8 and 133.2 (Ar-C), 135.2 (Ar-CH), 135.4 (C-7 or
-6), 175.3 (C-3).
(1R,5R,8R)-8-Acetoxy-2-oxabicyclo[3.3.0]oct-6-en-3-one 4
To a solution of bromo acetate 31 (4.77 g, 18.1 mmol) in dry
THF (40 ml) was added DBU (4.0 ml, 27.3 mmol) and the
mixture was heated to reflux for 16 h. The reaction mixture was
cooled to rt and concentrated to give a residue, which was
dissolved in water (25 ml) and extracted with dichloromethane
(5 × 40 ml). The combined organic phases were washed with
1 M HCl (2 × 25 ml) followed by re-extraction of the aqueous
phases with dichloromethane (25 ml). The combined organic
phases were washed with brine (25 ml), dried (MgSO4) and
concentrated to give a crude product (2.93 g, 88%), which was
purified by flash chromatography (EtOAc–hexane 1:1) to give
the title compound 4 as colourless crystals (2.74 g, 83%), mp
45–46 ЊC. Recrystallisation (Et2O) gave mp 49–50 ЊC; [α]D
Ϫ285.0 (c 1.00, CHCl3) (Found: C, 59.15; H, 5.5. Calc. for
C9H10O4: C, 59.3; H, 5.5%); δH(500 MHz; benzene-d6) 1.58
(3 H, s, CH3CO), 1.66 (1 H, dd, J4Ј,5 2.0, J4,4Ј 18.5, HЈ-4), 1.85
(1 H, dd, J4,5 10.5, J4,4Ј 18.5, H-4), 2.64 (1 H, m, H-5), 4.37 (1 H,
dd, J1,8 0.5, J1,5 6.0, H-1), 5.08 (1 H, dd, J 2.0, J6,7 5.5, H-6 or -7),
5.53 (1 H, ddt, J 0.5, J 2.0, J6,7 5.5, H-7 or -6), 5.58 (1 H, ddd,
J1,8 0.5, J 1.5, J 2.0, H-8); δC(62.5 MHz; CDCl3) 20.7 (CH3CO),
32.1 (C-4), 43.6 (C-5), 81.9 (C-8), 85.2 (C-1), 128.8 and 138.8
(C-6 ϩ -7), 169.8 (CH3CO), 175.1 (C-3).
(1R,5R,6R,7R,8S)-6,7,8-Triacetoxy-2-oxabicyclo[3.3.0]octan-
3-one 8 and (1R,5R,6S,7S,8S)-6,7,8-triacetoxy-2-oxabicyclo-
[3.3.0]octan-3-one 9
From compound 5. To a solution of compound 5 (99 mg, 2.78
mmol) in dry acetone (10 ml) was added NMO monohydrate
(194 mg, 1.40 mmol) together with a catalytic amount of OsO4
and the mixture was stirred at rt for 16 h. Na2SO3 (127 mg) was
added and the mixture was stirred for 0.5 h and then concen-
trated and co-concentrated with toluene to give a residue, which
was dissolved in pyridine (5 ml) and cooled to 0 ЊC. Acetic
anhydride (2.0 ml, 21.1 mmol) was then added and the reaction
mixture was stirred at rt for 16 h. Ice–water (10 ml) was added
and the mixture was stirred for 0.5 h, followed by extraction
with dichloromethane (3 × 25 ml). The combined organic
phases were washed with 1 M HCl (2 × 20 ml) followed by
re-extraction of the aqueous phases with dichloromethane
(10 ml). The combined organic phases were dried (MgSO4) and
concentrated to give a crude 3:1 mixture of the two diastereo-
meric products. Separation by flash chromatography (EtOAc–
hexane 55:45) gave compound 8 (145 mg, 68%) mp 82–90 ЊC,
followed by compound 9 (48 mg, 23%) mp 112–118 ЊC.
(1R,5R,8R)-8-Hydroxy-2-oxabicyclo[3.3.0]oct-6-en-3-one 5
A solution of compound 4 (530 mg, 2.91 mmol) in acidic
methanol (10 ml; 1% v/v acetyl chloride in methanol) was
stirred at rt for 40 h. Concentration gave the title compound 5
as colourless crystals (407 mg, quant.), mp 63–65 ЊC. Recrystal-
lisation (EtOAc–hexane) gave mp 67–68 ЊC; [α]D Ϫ170.9 (c 1.00,
CHCl3) (Found: C, 59.9; H, 5.8. Calc. for C7H8O3: C, 60.0; H,
5.75%); δH(500 MHz; benzene-d6) 1.66 (1 H, br s, OH), 1.71
(1 H, dd, J4Ј,5 2.0, J4,4Ј 18.0, HЈ-4), 1.89 (1 H, dd, J4,5 10.0, J4,4Ј
18.0, H-4), 2.75 (1 H, m, H-5), 4.33 (1 H, d, J1,5 6.0, H-1), 4.45
(1 H, br s, H-8), 5.07 (1 H, dd, J 2.0, J6,7 5.5, H-6 or -7), 5.42
(1 H, dt, J 2.0, J6,7 5.5, H-7 or -6); δC(62.5 MHz; CDCl3) 32.3
(C-4), 43.3 (C-5), 79.7 (C-8), 88.4 (C-1), 131.8 and 136.4
(C-6 ϩ -7), 176.5 (C-3).
(1R,5R,8R)-8-Benzoyloxy-2-oxabicyclo[3.3.0]oct-6-en-3-one 6
To a solution of compound 5 (396 mg, 2.83 mmol) in pyridine
Compound 8: Recrystallisation (EtOAc–hexane) gave mp
90–93 ЊC; [α]D Ϫ64.9 (c 1.00, CHCl3) (Found: C, 51.7; H, 5.2.
3618
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Calc. for C13H16O8: C, 52.0; H, 5.4%); δH(500 MHz; CDCl3)
2.07 (3 H, s, CH3CO), 2.09 (3 H, s, CH3CO), 2.11 (3 H, s,
CH3CO), 2.68 (1 H, dd, J4Ј,5 4.0, J4,4Ј 19.0, HЈ-4), 2.87 (1 H, dd,
J4,5 11.0, J4,4Ј 19.0, H-4), 3.16 (1 H, m, H-5), 5.00 (1 H, dd, J1,8
4.5, J1,5 9.5, H-1), 5.06 (1 H, dd, J6,7 4.0, J5,6 7.0, H-6), 5.24 (1 H,
dd, J7,8 4.0, J1,8 4.5, H-8), 5.56 (1 H, t, J6,7 = J7,8 4.0, H-7);
δC(62.5 MHz; CDCl3) 20.3 and 20.4 (3 × COCH3), 32.4 (C-4),
40.2 (C-5), 71.9 (C-7), 75.4 (C-8), 75.8 (C-6), 83.1 (C-1), 169.2,
169.4 and 169.8 (3 × COCH3), 175.2 (C-3).
Compound 9: Recrystallisation (EtOAc–hexane) gave mp
121–122.5 ЊC; [α]D Ϫ17.6 (c 1.00, CHCl3) (Found: C, 52.2; H,
5.2%); δH(500 MHz; CDCl3) 2.05 (3 H, s, CH3CO), 2.11 (3 H, s,
CH3CO), 2.12 (3 H, s, CH3CO), 2.60–2.62 (2 H, m, H2-4), 3.33
(1 H, m, H-5), 4.80 (1 H, dd, J1,8 1.5, J1,5 8.0, H-1), 5.29 (1 H,
dd, J6,7 4.0, J7,8 5.5, H-7), 5.32 (1 H, dd, J1,8 1.5, J7,8 5.5, H-8),
5.56 (1 H, dd, J6,7 4.0, J5,6 6.5, H-6); δC(62.5 MHz; CDCl3) 19.8
and 20.1 (3 COCH3), 28.1 (C-4), 37.0 (C-5), 71.7 (C-6), 74.4
(C-7), 77.6 (C-8), 83.8 (C-1), 168.9, 169.0 and 169.1 (3 ×
COCH3), 175.2 (C-3).
(C-4), 39.5 (C-5), 59.7 and 60.2 (C-6 ϩ -7), 77.6 (C-8), 88.9
(C-1), 175.2 (C-3).
(rac)-6,7,8-Trihydroxy-2-oxabicyclo[3.3.0]octan-3-one 12
To a solution of compound 11 (131 mg, 0.839 mmol) in water
(10 ml) was added perchloric acid (60%; 6 drops) and the mix-
ture was stirred at rt for 40 h. The reaction mixture was neutral-
ised with ion-exchange resin (Amberlite IRA-67, OHϪ, 5 ml),
filtered, and the resin was washed with water. The combined
water phases were concentrated to give a 50:1 mixture of the
title compound 12 and the 6,7-diepi-isomer (148 mg, 99%), mp
102–106 ЊC. Recrystallisation (EtOH) gave pure title compound
12 as colourless crystals (104 mg, 71%); mp 107–109 ЊC; [α]D 0.0
(c 1.00, MeOH) (Found: C, 48.0; H, 5.7. Calc. for C7H10O5: C,
48.3; H, 5.8%); δH(500 MHz; D2O) 2.64 (2 H, m, H2-4), 3.19
(1 H, m, H-5), 3.95 (1 H, dd, J7,8 4.5, J6,7 6.0, H-7), 4.11 (1 H,
dd, 1H, J1,8 2.5, J7,8 4.5, H-8), 4.12 (1 H, dd, J6,7 6.0, J5,6 7.5,
H-6), 4.76 (1 H, dd, J1,8 2.5, J1,5 8.0, H-1); δC(62.5 MHz; D2O)
28.1 (C-4), 38.2 (C-5), 73.9, 74.6 and 75.8 (C-6, -7 ϩ -8), 88.1
(C-1), 181.3 (C-3).
From compound 4. Compound 4 (96 mg, 0.537 mmol) was
dihydroxylated followed by acetylation according to the above
procedure to give a 1:3 mixture of the two diastereomeric com-
pounds. Separation by flash chromatography (EtOAc–hexane
55:45) gave compound 8 (30 mg, 19%), mp 81–88 ЊC, followed
by compound 9 (93 mg, 59%), mp 120–121 ЊC. 1H and 13C NMR
data as described above.
(1R,5R,6S,7R,8S)-6-Azido-7,8-isopropylidenedioxy-2-oxa-
bicyclo[3.3.0]octan-3-one 13 and (1R,5R,6R,7S,8R)-7-azido-6,8-
dihydroxy-2-oxabicyclo[3.3.0]octan-3-one 14
To a solution of compound 11 (401 mg, 2.57 mmol) in DMF
(10 ml) were added NaN3 (497 mg, 7.64 mmol) and NH4Cl (391
mg, 7.31 mmol) and the mixture was stirred at 55 ЊC for 40 h.
After cooling to rt the reaction mixture was concentrated and
the residue was dissolved in water (25 ml) and extracted with
EtOAc (6 × 40 ml). The combined organic phases were washed
with brine (20 ml), dried (MgSO4) and concentrated to give
a 6:1 mixture of the two isomeric azides (360 mg, 70%). The
mixture was dissolved in dry acetone (40 ml), treated with
MgSO4 (25.0 g) and H2SO4 (96%; 1 drop) and the solution was
stirred at rt for 40 h. The reaction mixture was neutralised with
solid NaHCO3, filtered and concentrated to give a 6:1 mixture
of unprotected and protected azides (310 mg). Separation by
flash chromatography (EtOAc–hexane 75:25) gave compound
13 (37 mg, 6.0%) followed by compound 14 (235 mg, 46%, 1%
unprotected 13 as seen from 13C NMR), which was recrystal-
lised (EtOAc) to give pure compound 14 (176 mg, 34%).
Compound 13: mp 81–82 ЊC; [α]D Ϫ128.0 (c 1.26, CHCl3)
(Found: C, 50.4; H, 5.5; N, 17.3. Calc. for C10H13N3O4: C, 50.2;
H, 5.5; N, 17.6%); δH(500 MHz; CDCl3) 2.19 [3 H, s, (CH3)2C],
2.30 [3 H, s, (CH3)2C], 3.47–3.49 (2 H, m, H2-4), 4.16 (1 H, m,
H-5), 5.08 (1 H, d, J5,6 6.0, H-6), 5.52 (1 H, d, J1,5 6.0, H-1), 5.63
(1 H, d, J7,8 5.0, H-7 or -8), 5.69 (1 H, d, J7,8 5.0, H-8 or -7);
δC(62.5 MHz; CDCl3) 24.3 and 26.4 [2 × (CH3)2C], 30.3 (C-4),
40.9 (C-5), 67.1 (C-6), 83.1 and 84.1 (C-7 ϩ -8), 88.9 (C-1),
111.7 [(CH3)2C], 175.2 (C-3).
(1R,5R,6S,7S,8R)-8-(tert-Butyldiphenylsilyloxy)-6,7-dihydroxy-
2-oxabicyclo[3.3.0]octan-3-one 10
Compound 7 (486 mg, 1.28 mmol) was dihydroxylated accord-
ing to the procedure for the preparation of compounds 8 and 9.
After concentration the residue was dissolved in 1 M HCl sat-
urated with NaCl (10 ml) and extracted with dichloromethane
(4 × 25 ml). The combined organic phases were washed succes-
sively with sat. aq. NaHCO3 (25 ml) and brine (25 ml), dried
(MgSO4) and concentrated to give a crude 13:1 mixture of the
two diastereomeric products. Separation by flash chromato-
graphy (EtOAc–hexane 6:4) gave the title compound 10 as
colourless crystals (280 mg, 53%), mp 132–133 ЊC. Recrystallis-
ation (toluene) gave mp 136–137 ЊC; [α]D Ϫ20.1 (c 0.37, CHCl3);
δH(500 MHz; benzene-d6–CDCl3 1:1) 1.12 [9 H, s, C(CH3)3],
1.86 (1 H, dd, J4,5 11.0, J4,4Ј 18.0, HЈ-4), 2.24 (1 H, m, H-5), 2.52
(1 H, dd, J4Ј,5 3.0, J4,4Ј 18.0, HЈ-4), 3.66 (1 H, t, J6,7 = J7,8 4.0,
H-7), 3.84 (1 H, dd, J6,7 4.0, J5,6 6.5, H-6), 4.29 (1 H, dd,
J1,8 1.5, J7,8 4.0, H-8), 4.33 (1 H, dd, J1,8 1.5, J1,5 8.0, H-1),
7.21–7.26 (6 H, m, ArH), 7.67–7.70 (4 H, m, ArH); δC(62.5
MHz; CDCl3) 19.0 [C(CH3)3], 26.7 (C(CH3)3), 29.7 (C-4), 38.4
(C-5), 72.3 (C-6), 78.4 (C-7), 80.2 (C-8), 88.4 (C-1), 127.7 and
129.9 (Ar-CH), 132.7 and 132.9 (Ar-C), 135.5 (Ar-CH), 178.1
(C-3).
Compound 14: mp 107–108 ЊC; [α]D Ϫ33.7 to Ϫ11.9 (5 min
to 5 days) (c 1.01 MeOH) (Found: C, 42.4; H, 4.65; N, 21.0.
Calc. for C7H9N3O4: C, 42.2; H, 4.55; N, 21.1%); δH(500 MHz;
MeOH-d4) 2.50 (1 H, dd, J4Ј,5 2.0, J4,4Ј 17.5, HЈ-4), 2.78 (1 H, m,
(1R,5R,6R,7R,8S)-6,7-Epoxy-8-hydroxy-2-oxabicyclo[3.3.0]-
octan-3-one 11
To a solution of compound 5 (1.19 g, 8.48 mmol) in dry
dichloromethane (30 ml) were added VO(acac)2 (30 mg, cat.)
and TBHP19 (4.1 M in toluene; 2.4 ml, 9.84 mmol) and the
mixture was heated to reflux for 4 h. The reaction mixture was
cooled to rt and concentrated to give a crude crystalline prod-
uct, which was quickly recrystallised from ethanol to give the
title compound 11 as slightly yellow crystals (1.07 g, 81%), mp
110–113 ЊC. Further recrystallisation (EtOH) gave mp 114–
115 ЊC; [α]D Ϫ24.2 (c 1.00, MeOH) (Found: C, 53.7; H, 5.2.
Calc. for C7H8O4: C, 53.85; H, 5.2%); δH(500 MHz; CDCl3) 2.30
(1 H, d, J8,OH 8.5, OH), 2.41 (1 H, dd, J4Ј,5 7.0, J4,4Ј 18.5, HЈ-4),
2.75 (1 H, dd, J4,5 11.0, J4,4Ј 18.5, H-4), 3.33 (1 H, dt, J1,5 = J4Ј,5
7.0, J4,5 11.0, H-5), 3.61 (1 H, d, J6,7 2.5, H-6 or -7), 3.76 (1 H,
t, J6,7 = J7,8 2.5, H-7 or -6), 4.36 (1 H, br d, J8,OH 8.5, H-8),
4.55 (1 H, dd, J1,8 2.0, J1,5 7.0, H-1); δC(62.5 MHz; CDCl3) 29.7
H-5), 2.83 (1 H, dd, J4,5 10.5, J4,4Ј 17.5, H-4), 3.52 (1 H, t, J6,7
=
J7,8 9.0, H-7), 3.66 (1 H, t, J5,6 = J6,7 9.0, H-6), 3.84 (1 H, dd,
J1,8 4.0, J7,8 9.0, H-8), 4.67 (1 H, dd, J1,8 4.0, J1,5 8.5, H-1);
δC(62.5 MHz; MeOH-d4) 33.7 (C-4), 42.9 (C-5), 72.4 (C-7), 78.7
(C-6), 79.2 (C-8), 87.7 (C-1), 190.0 (C-3).
(1R,5R,6R,7R,8R)-6,7,8-Trihydroxy-2-oxabicyclo[3.3.0]octan-
3-one 15
Compound 8 (140 mg, 0.47 mmol) was deacetylated according
to the procedure for 5. Concentration gave the title compound
15 as colourless crystals (75 mg, 93%), mp 116–117 ЊC.
Recrystallisation (EtOH) gave mp 117–118 ЊC; [α]D Ϫ30.8 (c
0.38, MeOH) (Found: C, 48.45; H, 5.9. Calc. for C7H10O5: C,
48.3; H, 5.8%); δH(500 MHz; D2O) 2.50 (1 H, dd, J4Ј,5 3.5, J4,4Ј
J. Chem. Soc., Perkin Trans. 1, 1999, 3615–3622
3619

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19.0, HЈ-4), 2.86 (1 H, dd, J4,5 11.0, J4,4Ј 19.0, H-4), 2.94 (1 H, m,
H-5), 3.93 (1 H, dd, J6,7 4.0, J5,6 7.5, H-6), 3.98 (1 H, t, J6,7
J7,8 4.0, H-7), 4.05 (1 H, dd, J7,8 4.0, J1,8 4.5, H-8), 4.83 (1 H, dd,
J1,8 4.5, J1,5 9.0, H-1); δC(62.5 MHz; D2O) 32.7 (C-4), 41.7 (C-5),
74.0, 76.2 and 76.4 (C-6, -7 ϩ -8), 89.4 (C-1), 181.0 (C-3).
Compound 18: Further recrystallisation (EtOH) gave mp
=
146–149 ЊC; [α]D Ϫ41.0 to Ϫ17.2 (5 min to 4 days) (c 0.57,
MeOH) (Found: C, 48.2; H, 5.6. Calc. for C7H10O5: C, 48.3; H,
5.8%); δH(500 MHz; D2O) 2.61–2.64 (2 H, m, H2-4), 3.02 (1 H,
m, H-5), 3.84 (1 H, dd, J6,7 4.0, J7,8 8.0, H-7), 4.01 (1 H, dd, J6,7
4.0, J5,6 5.5, H-6), 4.08 (1 H, dd, J1,8 3.0, J7,8 8.0, H-8), 4.70 (1 H,
dd, J1,8 3.0, J1,5 8.0, H-1); δC(62.5 MHz; D2O) 28.7 (C-4), 37.9
(C-5), 71.9, 77.1 and 79.3 (C-6, -7 ϩ -8), 88.9 (C-1), 181.5 (C-3).
Compound 19: δC(62.5 MHz; D2O) 27.8 (C-4), 36.6 (C-5),
71.4, 73.1 and 77.1 (C-6, -7 ϩ -8), 82.6 (C-1), 181.1 (C-3).
4a(R)-Acetoxy-1,2,3,6-tetra-O-acetyl-5-deoxy-4a-carba-ꢀ-D-
ribo-hexofuranose 16
Finely powdered calcium chloride (1.09 g, 9.82 mmol) and
sodium borohydride (720 mg, 19.0 mmol) were suspended in
ethanol (30 ml) and the mixture was stirred at Ϫ20 ЊC for 6 h to
ensure the formation of Ca(BH4)2. A solution of compound 15
(252 mg, 0.63 mmol) in ethanol (10 ml) was added and the
reaction mixture was stirred at rt for 16 h. The reaction mixture
was carefully quenched with 4 M HCl (10 ml) and stirred for
0.5 h, followed by concentration and coevaporation twice with
methanol. The crystalline residue was dissolved in water (50 ml)
and then loaded onto a column of ion-exchange resin (Amber-
lite IR-120, Hϩ, 125 ml). The column was eluted with water
(250 ml) to neutral pH, after which the aqueous phases were
concentrated to give the crude pentahydroxy compound. This
was dissolved in acetic anhydride (10 ml), perchloric acid was
added (60%, 1 drop) and the mixture was stirred for 1.5 h.
Concentration gave an oil, which was dissolved in dichloro-
methane (40 ml) and washed successively with water (20 ml)
and sat. aq. NaHCO3 (2 × 20 ml). The aqueous phases were
re-extracted with dichloromethane (10 ml) and the combined
organic phases were washed with brine (20 ml), dried (MgSO4)
and concentrated to give a crude product (615 mg, quant.).
Purification by flash chromatography (EtOAc–hexane 45:55)
gave the title compound 16 as a colourless oil (470 mg, 84%),
[α]D ϩ17.8 (c 0.84, CHCl3) (Found: C, 52.3; H, 5.9. Calc. for
C17H24O10: C, 52.6; H, 6.2%); δH(500 MHz; CDCl3) 1.71 (1 H,
From compound 10. To a solution of compound 10 (404 mg,
1.07 mmol) in THF (20 ml) was added TBAF (2 ml; 1 M in
THF) and the mixture was stirred at rt for 40 h. The reaction
mixture was treated with water (10 ml) and washed with EtOAc
(3 × 25 ml). The aqueous phase was then loaded onto a column
of ion-exchange resin (Amberlite IR-120, Hϩ, 20 ml) and eluted
with water (50 ml) to neutral pH. The aqueous phase was con-
centrated to give a crude product, which was purified by flash
chromatography (EtOAc–methanol 8:2) to give the title prod-
ucts 18 and 19 as a crystalline 3:1 mixture (110 mg, 59%), mp
116–145 ЊC. 13C NMR data as described above.
4a(R)-Acetoxy-1,2,3,6-tetra-O-acetyl-5-deoxy-4a-carba-ꢁ-D-
lyxo-hexofuranose 20
Reduction and acetylation of compounds 18 and 19 (3:1 mix-
ture; 119 mg, 0.683 mmol) was done according to the procedure
for 16. Purification by flash chromatography (EtOAc–hexane
45:55) gave the title compound 20 as a colourless oil (188 mg,
71%); [α]D ϩ 24.4 (c 0.93, CHCl3) (Found: C, 52.3; H, 6.0. Calc.
for C17H24O10: C, 52.6; H, 6.2%); δH(500 MHz; CDCl3) 1.71
(1 H, dq, J4,5Ј = J5Ј,6 = J5Ј,6Ј 5.0, J5,5Ј 11.5, HЈ-5), 1.76 (1 H,
ddt, J5,6 = J5,6Ј 5.0, J4,5 6.5, J5,5Ј 11.5, H-5), 2.01 (3 H, s,
CH3CO), 2.02 (3 H, s, CH3CO), 2.06 (3 H, s, CH3CO), 2.11
(3 H, s, CH3CO), 2.13 (3 H, s, CH3CO), 2.54 (1 H, m, H-4), 4.01
(2 H, m, H2-6), 5.18 (1 H, dd, J 4.0, J 8.0, H-3 or -4a), 5.27 (1 H,
dd, J 3.0, J 8.0, H-1 or -2), 5.38 (1 H, dd, J 3.0, J 8.0, H-4a or
-3), 5.44 (1 H, t, J 4.0, J 4.0, H-2 or -1); δC(62.5 MHz; CDCl3)
20.3, 20.4, 20.5 and 20.5 (5 × COCH3), 22.4 (C-5), 38.7 (C-4),
62.0 (C-6), 72.7, 75.0, 75.2 and 80.8 (C-1, -2, -3 ϩ -4a), 169.8,
169.9, 170.0 and 170.6 (5 × COCH3).
dq, J4,5Ј = J5Ј,6 = J5Ј,6Ј 6.5, J5,5Ј 14.0, HЈ-5), 1.84 (1 H, ddt, J5,6
=
J5,6Ј 6.5, J4,5 7.0, J5,5Ј 14.0, H-5), 2.04 (3 H, s, CH3CO), 2.05
(3 H, s, CH3CO), 2.07 (3 H, s, CH3CO), 2.08 (3 H, s, CH3CO),
2.11 (3 H, s, CH3CO), 2.63 (1 H, m, H-4), 4.03 (1 H, dt, J5,6Ј
=
J5Ј,6Ј 6.5, J6,6Ј 11.0, HЈ-6), 4.10 (1 H, dt, J5,6 = J5Ј,6 6.5, J6,6Ј 11.0,
H-6), 5.08 (1 H, dd, J 4.5, J 9.0, H-3 or -4a), 5.16 (1 H, t, J 4.5,
H-1 or -2), 5.38 (1 H, dd, J 4.0, J 8.0, H-4a or -3), 5.51 (1 H, t,
J 5.0, H-2 or -1); δC(62.5 MHz; CDCl3) 19.8, 19.9, 19.9, 20.1
and 20.2 (5 COCH3), 25.4 (C-5), 40.1 (C-4), 61.8 (C-6), 69.3,
73.6, 74.3 and 76.9 (C-1, -2, -3 ϩ -4a), 168.8, 168.8, 169.2, 169.3
and 170.1 (5 × COCH3).
5-Deoxy-4a(R)-hydroxy-4a-carba-ꢀ-D-lyxo-hexofuranose 21
Compound 20 (109 mg, 0.28 mmol) was deacetylated according
to the procedure for 17. Concentration gave the title compound
21 as colourless crystals (50 mg, quant.), mp 126–128 ЊC.
Recrystallisation (MeOH) gave mp 131–134 ЊC; [α]D ϩ 29.0 (c
0.30, H2O) (Found: C, 47.0; H, 7.7. Calc. for C7H12O5: C, 47.2;
H, 7.9%); δH(500 MHz; MeOH-d4) 1.83 (2 H, m, H2-5), 2.11
(1 H, m, H-4), 3.68 (2 H, ddt, J 6.5, J 10.5, J6,6Ј 13.5, H2-6), 3.72
(1 H, dd, J 4.0, J 6.0, H-1 or -2), 3.81 (1 H, dd, J 2.5, J 6.5, H-3
or -4a), 3.93 (1 H, t, J 4.0, H-4a or -3), 3.97 (1 H, dd, J 2.5,
J 6.0, H-2 or -1); δC(62.5 MHz; MeOH-d4) 27.3 (C-5), 42.0
(C-4), 61.6 (C-6), 75.8, 79.8, 78.8 and 88.4 (C-1, -2, -3 ϩ -4a).
5-Deoxy-4a(R)-hydroxy-4a-carba-ꢀ-D-ribo-hexofuranose 17
Compound 16 (223 mg, 0.57 mmol) was deacetylated according
to the procedure for 5. The solution was then neutralised with
ion-exchange resin (Amberlite IRA-67, OHϪ, 5 ml), filtered and
the resin was washed with methanol. The combined methanol
phases were concentrated to give the title compound 17 as a
colourless oil (82 mg, 80%), [α]D ϩ26.7 (c 2.4, H2O) (Found: C,
47.2; H, 7.6. Calc. for C7H12O5: C, 47.2; H, 7.9%); δH(500 MHz;
D2O) 1.53 (1 H, ddt, J 7.0, J 8.0, J5,5Ј 14.0, HЈ-5), 1.70 (1 H, ddt,
J 7.0, J 8.0, J5,5Ј 14.0, H-5), 2.03 (1 H, m, H-4), 3.56–3.60 (2 H,
m, H2-6), 3.71 (1 H, dd, J 4.5, J 9.0, H-3 or -4a), 3.78 (1 H, t,
J 5.0, H-1 or -2), 3.91 (1 H, dd, J 4.5, J 5.0, H-2 or -1), 4.01 (1 H,
dd, J 5.0, J 8.5, H-4a or -3); δC(62.5 MHz; D2O) 29.7 (C-5), 43.1
(C-4), 60.5 (C-6), 71.6, 75.0, 75.3 and 77.4 (C-1, -2, -3 ϩ -4a).
4a(R)-Acetoxy-1,2,3,6-tetra-O-acetyl-5-deoxy-4a-carba-ꢀ-D-
xylo-hexofuranose 22
Reduction and acetylation of compound 12 (239 mg, 1.37
mmol) was done according to the procedure for 16. Purification
by flash chromatography (EtOAc–hexane 45:55) gave the title
compound 22 as colourless crystals (440 mg, 83%), mp 86–
87 ЊC. Recrystallisation (toluene) gave mp 88.5–90 ЊC; [α]D 0.0
(c 1.00, CHCl3) (Found: C, 52.6; H, 6.15. Calc. for C17H24O10:
C, 52.6; H, 6.2%); δH(500 MHz; benzene-d6) 1.62 (6 H, s,
CH3CO), 1.65 (3 H, s, CH3CO), 1.66 (2 H, q, J 7.0, H2-5), 1.66
(6 H, s, CH3CO), 2.59 (1 H, quintet, J 7.0, H-4), 3.92 (2 H, t,
J 7.0, H2-6), 5.50 (2 H, ddd, J 0.5, J 2.0, J 7.0, H-3 ϩ -4a), 5.64
(2 H, dd, J 0.5, J 2.0, H-1 ϩ -2); δC(62.5 MHz; CDCl3) 20.1,
(1R,5R,6S,7S,8R)-6,7,8-Trihydroxy-2-oxabicyclo[3.3.0]octan-
3-one 18 and (1S,5S,6R,7S,8R)-6,7,8-trihydroxy-2-oxabicyclo-
[3.3.0]octan-3-one 19
From compound 9. Compound 9 (86 mg, 0.286 mmol) was
deacetylated according to the procedure for 17. Concentration
gave a 3:1 mixture of the title compounds 18 and 19 as an oil
(50 mg, quant.). Crystallisation (EtOH) gave pure compound
18 as colourless crystals (23 mg, 46%), mp 144–147 ЊC.
3620
J. Chem. Soc., Perkin Trans. 1, 1999, 3615–3622

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20.4 and 20.4 (5 × COCH3), 22.3 (C-5), 38.8 (C-4), 62.2 (C-6),
75.0 and 75.5 (C-1, -2, -3 ϩ -4a), 169.0, 169.5 and 170.4 (5 ×
COCH3).
less oil (44 mg, 47%), [α]D ϩ37.6 (c 1.6, CHCl3) (Found: C,
48.5; H, 5.7; N, 11.1. Calc. for C15H21N3O8: C, 48.5; H, 5.7; N,
11.3%); δH(500 MHz; CDCl3) 1.69 (1 H, dq, J4,5Ј = J5Ј,6
=
J5Ј,6Ј 6.5, J5,5Ј 14.5, HЈ-5), 1.81 (1 H, ddt, J5,6 = J5,6Ј 6.5, J4,5 8.5,
J5,5Ј 14.5, H-5), 2.01 (3 H, s, CH3CO), 2.10 (3 H, s, CH3CO),
2.11 (6 H, s, 2 × CH3CO), 2.38 (1 H, m, H-4), 3.71 (1 H, ddd,
J2,4 1.0, J1,2 4.0, J2,3 6.5, H-2), 3.97–4.07 (2 H, m, H2-6), 4.85
(1 H, dd, J1,4a 2.0, J4,4a 6.0, H-4a), 5.11 (1 H, dd, J2,3 6.5, J4,3
10.0, H-3), 5.14 (1 H, dd, J1,4a 2.0, J1,2 4.0, H-1); δC(62.5 MHz;
CDCl3) 20.5, 20.6, 20.7 and 20.7 (4 × COCH3), 24.9 (C-5), 42.3
(C-4), 62.1 (C-6), 69.5 (C-2), 74.7, 78.8 and 79.5 (C-1, -3 ϩ -4a),
169.3, 169.5, 170.0 and 170.7 (4 × COCH3).
5-Deoxy-4a(R)-hydroxy-4a-carba-ꢀ-D-xylo-hexofuranose 23
Compound 22 (120 mg, 0.31 mmol) was deacetylated according
to the procedure for 17. Concentration gave the title compound
23 as a colourless oil (44 mg, 80%); [α]D 0.0 (c 0.84, MeOH)
(Found: C, 47.0; H, 8.1. Calc. for C7H12O5: C, 47.2; H, 7.9%);
δH(500 MHz; MeOH-d4) 1.76 (2 H, dt, J 6.5, J 7.0, H2-5), 2.35
(1 H, tt, J 6.0, J 7.5, H-4), 3.67 (2 H, t, J 6.5, H2-6), 3.94 (2 H,
dd, J 2.0, J 6.0, H-3 ϩ -4a), 4.00 (2 H, d, J 2.0, H-1 ϩ -2);
δC(62.5 MHz; MeOH-d4) 27.7 (C-5), 42.3 (C-4), 62.2 (C-6), 79.0
and 79.3 (C-1, -2, -3 ϩ -4a).
2-Azido-2,5-dideoxy-4a(R)-hydroxy-4a-carba-ꢀ-D-arabino-
hexofuranose 28
(1R,5R,6R,7S,8R)-7-Amino-6,8-dihydroxy-2-oxabicyclo[3.3.0]-
octan-3-one hydrochloride 24
From compound 14. Reduction of compound 14 (51 mg,
0.256 mmol) was done according to the procedure for 27. The
reaction mixture was then carefully quenched with 1 M HCl
(5 ml) and stirred for 1 h followed by concentration and
coevaporation twice with methanol to give a crude product
(quant.). Purification by flash chromatography (7.5% methanol
in EtOAc) gave the title compound 28 as a colourless, hygro-
scopic oil (23 mg, 44%), [α]D ϩ44.4 (c 0.89, MeOH); δH(500
MHz; MeOH-d4) 1.50 (1 H, dq, J4,5Ј = J5Ј,6 = J5Ј,6Ј 6.5, J5,5Ј
14.0, HЈ-5), 1.81 (1 H, ddt, J5,6 = J5,6Ј 6.5, J4,5 8.0, J5,5Ј 14.0,
H-5), 1.89 (1 H, m, H-4), 3.33 (1 H, dd, J1,2 7.5, J2,3 8.5, H-2),
3.46–3.54 (2 H, m, H2-6), 3.55 (1 H, dd, J2,3 8.5, J4,3 9.5, H-3),
3.59 (1 H, dd, J1,4a 4.5, J1,2 7.5, H-1), 3.85 (1 H, dd, J1,4a 4.5, J4a,4
8.0, H-4a); δC(62.5 MHz; MeOH-d4): 28.8 (C-5), 43.1 (C-4),
60.0 (C-6), 71.3, 74.2, 77.0 and 79.7 (C-1, -2, -3 ϩ -4a).
To a solution of compound 14 (142 mg, 0.713 mmol) in acidic
ethanol (ethanol 5 ml ϩ 12 M HCl 0.5 ml) was added Pd/C (30
mg) and the mixture was stirred at rt in a hydrogen atmosphere
for 16 h. Filtration through a pad of Celite and concentration
gave the title compound 24 as a colourless, hygroscopic foam
(149 mg, quant.); [α]D Ϫ31.8 (c 1.0, MeOH); δH(500 MHz;
MeOH-d4) 2.59 (1 H, m, HЈ-4), 2.80–2.96 (2 H, m, H-4 ϩ -5),
3.23 (1 H, dd, J7,8 9.5, J6,7 10.0, H-7), 3.87 (1 H, dd, J5,6 7.5, J6,7
10.0, H-6), 4.58 (1 H, dd, J1,8 4.0, J7,8 9.5, H-8), 4.73 (1 H, dd,
J1,8 4.0, J1,5 6.0, H-1); δC(62.5 MHz; MeOH-d4) 35.8 (C-4), 45.8
(C-5), 64.7 (C-7), 78.5 and 79.5 (C-6 ϩ -8), 90.0 (C-1), 180.7
(C-3).
2-Acetamido-4a(R)-acetoxy-1,3,6-tri-O-acetyl-2,5-dideoxy-4a-
carba-ꢀ-D-arabino-hexofuranose 25
From compound 27. Compound 27 (44 mg, 0.118 mmol) was
deacetylated according to the procedure for 17. Concentration
gave the title compound 28 as a colourless, hygroscopic oil (24
mg, quant.). 1H NMR and 13C NMR data as described above.
Reduction of compound 24 (66 mg, 0.316 mmol) was done
according to the procedure for 16. The crystalline residue was
dissolved in water (50 ml) and loaded onto a column of ion-
exchange resin (Amberlite IR-120, Hϩ, 100 ml). The column
was eluted with water (200 ml) to neutral pH followed by 12.5%
aq. NH3 (200 ml) and the alkaline phases were concentrated
to give the crude aminohydroxy compound. This was then
acetylated according to the procedure for compound 16 and
concentrated to give a crude product (106 mg, 86%). Purifi-
cation by flash chromatography (EtOAc) gave a 12:1 mixture
of the title compound 25 and the bicyclic amine 26 (60 mg,
49%). Recrystallisation (toluene–ethanol) gave the pure title
compound 25 as colourless crystals (35 mg, 28%), mp 95–96 ЊC;
[α]D ϩ27.2 (c 3.50, CHCl3) (Found: C, 52.4; H, 6.2; N, 3.6.
Calc. for C17H25NO9: C, 52.7; H, 6.5; N, 3.6%); δH(500 MHz;
CDCl3) 1.71 (1 H, dq, J4,5Ј = J5Ј,6 = J5Ј,6Ј 6.5, J5,5Ј 14.5, HЈ-5),
1.81 (1 H, ddt, J5,6 = J5,6Ј 6.5, J4,5 8.5, J5,5Ј 14.5, H-5), 1.95
(3 H, s, CH3CO), 2.04 (3 H, s, CH3CO), 2.09 (3 H, s, CH3CO),
2.10 (3 H, s, CH3CO), 2.12 (3 H, s, CH3CO), 2.47 (1 H, m, H-4),
4.02–4.11 (2 H, m, H2-6), 4.28 (1 H, dt, J1,2 6.0, J2,3 = J2,N 8.0,
H-2), 4.95 (1 H, dd, J1,4a 2.5, J4,4a 6.5, H-4a), 5.07 (1 H, dd, J2,3
8.0, J3,4 10.5, H-3), 5.19 (1 H, dd, J1,4a 2.5, J1,2 6.0, H-1), 5.87
(1 H, br d, J1,N 8.0, NH); δC(62.5 MHz; CDCl3) 20.7, 20.8, 20.8,
20.8 and 23.7 (5 × COCH3), 25.3 (C-5), 41.4 (C-4), 59.5 (C-2),
62.1 (C-6), 74.6, 78.1 and 79.5 (C-1, -3 ϩ -4a), 169.4, 169.8,
170.4, 170.8 and 171.2 (5 × COCH3).
2-Amino-2,5-dideoxy-4a(R)-hydroxy-4a-carba-ꢀ-D-arabino-
hexofuranose hydrochloride 1
Compound 28 (20 mg, 0.098 mmol) was hydrogenated accord-
ing to the procedure for 24 (acidic methanol was used instead of
acidic ethanol). Concentration gave the title compound 1 as a
colourless, hygroscopic foam (20 mg, 95%); [α]D ϩ30.9 (c 0.94,
MeOH) (Found: M ϩ H, 178.1083. C7H15NO4 requires M ϩ
H, 178.1079); δH(250 MHz; MeOH-d4) 1.70–1.94 (2 H, m,
H2-5), 2.07 (1 H, m, H-4), 3.05 (1 H, dd, J1,2 6.0, J2,3 8.0, H-2),
3.61–3.75 (2 H, m, H2-6), 3.80 (1 H, dd, J2,3 8.0, J4,3 10.0, H-3),
3.84 (1 H, dd, J1,4a 2.5, J1,2 6.0, H-1), 3.94 (1 H, dd, J1,4a 2.5, J4a,4
6.5, H-4a); δC(62.5 MHz; MeOH-d4) 30.4 (C-5), 47.3 (C-4), 61.7
(C-6), 64.8 (C-2), 77.2, 77.7 and 80.2 (C-1, -3 ϩ -4a).
References
1 Part I, S. K. Johansen, H. T. Kornø and I. Lundt, Synthesis, 1999,
171.
2 S. K. Johansen and I. Lundt, presented in part at the XIXth
International Carbohydrate Symposium (ICS XIX), San Diego,
CA, 1998 (abstract BP 221).
3 For the use of the carba prefix, see: C. Marschner, J. Baumgartner
and H. Griengl, J. Org. Chem., 1995, 60, 5224 and IUPAC rule:
2-carb-34.2 (Pure Appl. Chem., 1996, 68, 1919).
4 M. T. Crimmins, Tetrahedron, 1998, 54, 9229.
5 For a recent synthesis, see: Y. Tokoro and Y. Kobayashi, Chem.
Commun., 1999, 807.
4a(R)-Acetoxy-1,3,6-tri-O-acetyl-2-azido-2,5-dideoxy-4a-carba-
ꢀ-D-arabino-hexofuranose 27
A solution of Ca(BH4)2ؒ2THF (267 mg, 1.24 mmol) in dry
THF (20 ml) under argon was cooled to Ϫ20 ЊC and stirred for
5 min. Compound 14 (51 mg, 0.256 mmol) was then added and
the reaction mixture was stirred at Ϫ20 ЊC for 16 h. The reac-
tion mixture was then worked-up and acetylated according to
the procedure for 25. Purification by flash chromatography
(EtOAc–hexane 45:55) gave the title compound 27 as a colour-
6 For a recent synthesis, see: H. F. Olivo and J. Yu, J. Chem. Soc.,
Perkin Trans. 1, 1998, 391.
7 A. Toyota, N. Katagiri and C. Kaneko, Heterocycles, 1994, 38, 27.
8 A. Berecibar, C. Grandjean and A. Siriwardena, Chem. Rev., 1999,
99, 779; Carbohydrate Mimics, ed. Y. Chapleur, Wiley, Weinheim,
1998.
9 For a recent synthesis see: R. Ling, P. S. Mariano and B. Ganem,
J. Org. Chem., 1998, 63, 6072.
J. Chem. Soc., Perkin Trans. 1, 1999, 3615–3622
3621

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10 For a recent synthesis see: D. J. Kassab and B. Ganem, J. Org.
Chem., 1999, 64, 1782.
11 For a recent synthesis see: A. Boiron, P. Zillig, D. Faber and
B. Giese, J. Org. Chem., 1998, 63, 5877.
12 R. A. Farr, N. P. Peet and M. S. Kang, Tetrahedron Lett., 1990, 31,
7109.
13 A. Blaser and J.-L. Reymond, Helv. Chim. Acta, 1999, 82, 760.
14 A. M. Horneman, I. Lundt and I. Søtofte, Synlett, 1995, 918;
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Chem., 1998, 63, 1919.
15 I. Lundt, Top. Curr. Chem., 1997, 187, 117.
16 K. B. Sharpless and T. R. Verhoeven, Aldrichim. Acta, 1979, 12, 63.
17 S. Daluge and R. Vince, J. Org. Chem., 1978, 43, 2311.
18 S. Ogawa and K. Washida, Eur. J. Org. Chem., 1998, 1929.
19 Anhydrous TBHP was prepared following the procedure by J. G.
Hill, B. E. Rossiter and K. B. Sharpless, J. Org. Chem., 1983, 48,
3607.
Paper 9/07008G
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J. Chem. Soc., Perkin Trans. 1, 1999, 3615–3622