Synthesis of 1,6-anhydro-β-D-hexopyranoses fused to the piperidine ring

Article abstract of DOI:10.1135/cccc20051429

Two piperidine derivatives (6 and 17) containing fused 1,6-anhydro-β- D-hexopyranose moiety were prepared from 1,6-anhydro-β-D-glucopyranose (1). The first synthetic route led via the known 1,6:2,3-dianhydro-4-deoxy-4-(3- hydroxypropyl)-β-D-mannopyranose

Full text of DOI:10.1135/cccc20051429

1,6-Anhydro-β-D-hexopyranoses
1429
SYNTHESIS OF 1,6-ANHYDRO-β-D-HEXOPYRANOSES FUSED TO
THE PIPERIDINE RING
b,
a3
Tomáš TRTEKa1, Miloslav ČERNÝa2, Miloš BUDĚŠÍNSKÝ *, Tomáš TRNKA and
c
Ivana CÍSAŘOVÁ
a
Department of Organic Chemistry, Charles University,
1
Hlavova 2030, 128 40 Prague 2, Czech Republic; e-mail: tomastrtek@email.cz,
2
3
mila@natur.cuni.cz, trnka@natur.cuni.cz
b
c
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
Flemingovo nám. 2, 166 10 Prague 6, Czech Republic; e-mail: budesinsky@uochb.cas.cz
Department of Inorganic Chemistry, Charles University,
Hlavova 2030, 128 40 Prague 2, Czech Republic; e-mail: cisarova@natur.cuni.cz
Received April 15, 2005
Accepted May 31, 2005
Two piperidin e derivatives (6 an d 17) con tain in g fused 1,6-an h ydro-β-D-h exopyran ose m oi-
ety were prepared from 1,6-an h ydro-β-D-glucopyran ose (1). Th e first syn th etic route led via
th e kn own 1,6:2,3-dian h ydro-4-deoxy-4-(3-h ydroxypropyl)-β-D-m an n opyran ose (2) obtain ed
in four steps from 1. Its h ydroxyl group was con verted in to am in o group via tosylate an d
azide. Th e correspon din g am in o epoxide 5 readily rearran ged in to 3-am in o-1,6-an h ydro-
3,4-dideoxy-3-N,4-C-(propan e-1,3-diyl)-β-D-altropyran ose (6). Th e secon d route used th e
kn own 1,6-an h ydro-2,4-di-O-tosyl-β-D-ribo-h exopyran os-3-ulose (9) as an in term ediate. Addi-
tion of allylm agn esium ch loride to ketose 9 afforded 3-C-allyl-1,6-an h ydro-2,4-di-O-tosyl-
β-D-allopyran ose (10). Hydroboration of its double bon d followed by tran sform ation of th e
resultin g prim ary h ydroxyl group in to tosylam ido group gave tritosyl derivative 15.
In tram olecular replacem en t of th e tosyloxy group in position 4 by tosylam ido group gave
tosylated piperidin e derivative 16. Detosylation of 16 afforded th e target 4-am in o-
1,6-an h ydro-3,4-dideoxy-3-C,4-N-(propan e-1,3-diyl)-β-D-gulopyran ose (17).
Keyw ord s: Carboh ydrates; Heterocycles; 1,6-An h ydrosugars; Piperidin es; Oxiran es; Alkaloids;
Cyclization s; X-ray diffraction ; NMR spectroscopy; Con form ation an alysis.
Piperidin e-based com poun ds1 still attract atten tion because of th eir biologi-
cal sign ifican ce. Th e piperidin e rin g is on e of th e m ost com m on h etero-
cyclic m otives in th e structure of alkaloids an d syn th etic ph arm aceuticals.
Piperidin e alkaloids are based on substituted piperidin e rin g, often bearin g
alkyl ch ain (fun ction alized or n ot), h ydroxyl group, or an oth er rin g. Sugar-
derived alkaloids, possessin g glycosidase-in h ibitin g activities, usually in -
clude in th eir skeleton a h igh ly fun ction alised piperidin e rin g. An alogous
derivatives with m orph olin e or 1,4-oxazepan e rin g we described recen tly2,3
.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)
doi:10.1135/cccc20051429

1430
Trtek et al.:
In th e presen t paper, we report on th e syn th esis of two n itrogen carbo-
h ydrate derivatives based on piperidin e fused to th e pyran rin g of 1,6-
an h ydro-β-D-h exopyran ose in position s 3 an d 4. For th eir preparation were
used two syn th etic routes, both startin g from 1,6-an h ydro-β-D-gluco-
pyran ose (1) (levoglucosan )4.
Th e first route uses th e kn own 1,6:2,3-dian h ydro-4-deoxy-4-(3-h ydroxy-
propyl)-β-D-m an n opyran ose5 (2) wh ich was prepared from 1 via 1,6:3,4-di-
an h ydro-2-O-tosyl-β-D-galactopyran ose6 an d 4-allyl-1,6-an h ydro-4-deoxy-
2-O-tosyl-β-D-glucopyran ose7 in four steps. Th e h ydroxyl group of 2 was
tosylated an d th e resultin g tosyloxy group in 3 was replaced by azido group
in th e reaction of 3 with sodium azide in 83% yield. Catalytic h ydrogen a-
tion of th e azido derivative 4 gave th e correspon din g am in e 5 wh ich readily
rearran ged in to th e piperidin e derivative 6 in refluxin g m eth an ol. Th us, th e
con version 4 → 5 → 6 was perform ed to advan tage in on e-step procedure
givin g
3-am in o-1,6-an h ydro-3,4-dideoxy-3-N,4-C-(propan e-1,3-diyl)-
β-D-altropyran ose (6) in 64% yield. Acetolysis of 6 followed by Zem plén
deacetylation afforded a m ixture of th e correspon din g reducin g sugar 8
con tain in g two m ajor isom ers of th e α-an om er an d two m in or isom ers of
th e β-an om er (see NMR discussion ), an d N-acetylated startin g m aterial 7 in
th e 1:2 ratio (Sch em e 1).
O
O
O
OH
2: X = OH
3: X = OTs
4: X = N3
O
O
(i)
(ii)
(iii)
OH
OH
1
X
5: X = NH2
(iv)
O
CH2OH
O
OH
OH
(v)
O
OH
RN
AcN
6: R = H
(v)
8
7: R = Ac
SCHEME 1
(i) TsCl, py, r.t. (84%); (ii) NaN3, DMF, 60 °C (83%); (iii) H2, Pd/C, MeOH, r.t.; (iv) MeOH,
65 °C (64%); (v) TFA, Ac2O, r.t., th en MeONa, MeOH, r.t. (70%)
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1,6-Anhydro-β-D-hexopyranoses
1431
Th e secon d syn th etic route (Sch em e 2) leadin g to th e piperidin e deriva-
tive 17 uses as a startin g com poun d 1,6-an h ydro-2,4-di-O-tosyl-β-D-ribo-
h exopyran os-3-ulose (9) easily accessible by oxidation of 1,6-an h ydro-
2,4-di-O-tosyl-β-D-glucopyran ose with ch rom ium trioxide in acetic acid8. As
expected, stereoselective addition of allylm agn esium ch loride to th e car-
bon yl group of ketose 9 gave 3-C-allyl-1,6-an h ydro-2,4-di-O-tosyl-β-D-allo-
pyran ose (10) (64%) in agreem en t with an alogous reaction s9 of 9 with
m eth ylm agn esium iodide or ph en ylm agn esium ch loride (for com parison ,
see ref.8). Hydroboration of th e double bon d in 10 afforded th e diol 11 (in
77% yield). In an effort to prepare com poun d 14 via azide 13, we in ten ded
to use a sim ilar reaction sequen ce in cludin g reaction s 2 → 3 → 4 → 5 as
sh own in Sch em e 1. Surprisin gly, th e on ly product of th e tosylation step
perform ed with tosyl ch loride in pyridin e at room tem perature was th e
oxolan e spiro com poun d 12. Th is outcom e m ay be accoun ted for by ex-
pected preferen tial tosylation of th e prim ary h ydroxyl group followed by
rapid in tram olecular replacem en t of th e leavin g tosyloxy group by suitably
orien ted tertiary h ydroxyl group at C-3. (For an alogous reaction s, see th e
form ation of spirocyclic oxolan e derivatives of substituted cycloh exan es10.)
A sign ifican t role in th is reaction m igh t play a favorable en tropic factor
gen erally forcin g in tram olecular cyclization s th at result in th e form ation of
relatively stable five-m em bered rin gs. In con n ection with th e sm ooth for-
m ation of th e oxolan e rin g m en tion ed above, it is worth n otin g th at th e
tertiary h ydroxyl group of 11 resists acetylation with acetic an h ydride in
pyridin e solution un der usual reaction con dition s (for relevan t literature,
see ref.9).
In order to obtain azide 13, com poun d 11 was treated with h ydrogen
azide un der Mitsun obu reaction con dition s11. Th e obtain ed azido derivative
13 was reduced to give th e correspon din g am in e 14 wh ich was con verted to
th e tosyl derivative 15. In tram olecular substitution of th e tosyloxy group at
C-4 by th e tosylam ido group in 15 proceeded with h igh regioselectivity giv-
in g th e piperidin e derivative 16 in 69% yield. Such a reaction course is in
agreem en t with th e regioselective reaction of 1,6-an h ydro-2,4-di-O-tosyl-
β-D-glucopyran ose in alkalin e solution yieldin g 1,6:3,4-dian h ydro-2-O-
tosyl-β-D-galactopyran ose (for a detailed discussion , see ref.12). Detosylation
perform ed with sodium am algam in boilin g m eth an ol afforded th e target
4-am in o-1,6-an h ydro-4-deoxy-3-C,4-N-(propan e-1,3-diyl)-β-D-gulopyran ose
(17) in 65% yield.
An attem pt at acetolysis of 17 un der th e con dition s used for acetolysis of
com poun d 6 failed, an d N-acetylated startin g com poun d 18 was isolated as
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1432
Trtek et al.:
a sole product in 71% yield. On th e oth er h an d, prelim in ary experim en ts
on h ydrolysis of 17 usin g 6 M h ydroch loric acid at 100 °C were successful.
HO
O
O
O
(i)
(ii)
O
O
O
1
O
HO
OTs
HO
OTs
OTs
OTs
OTs
OTs
9
11
(iii)
10
(iv)
X
O
O
O
(vii)
O
O
O
R1N
O
OTs
HO
HO
OTs
OR2
OTs
OTs
16: R1 = R2 = Ts
17: R1 = R2 = H
18: R1 = Ac, R2 = H
13: X = N3
12
(v)
(viii)
(ix)
14: X = NH2
15: X = NHTs
(vi)
SCHEME 2
(i) H2C=CH–CH2MgCl, THF, 0 °C (64%); (ii) BH3, THF, r.t., th en H2O2, NaOH (77%); (iii) TsCl,
py, r.t. (79%); (iv) HN3, Ph 3P, iPrOOCN=NCOOiPr, THF, r.t. (95%); (v) H2, Pd/C, EtOH, r.t.
(73%); (vi) TsCl, Et3N, CH2Cl2, r.t. (71%); (vii) K2CO3, DMF, 110 °C (69%); (viii) Na-Hg,
Na2HPO4, MeOH, 65 °C (65%); (ix) TFA, Ac2O, r.t., th en MeONa, MeOH, r.t. (71%)
NMR DISCUSSION
Th e structure of com poun ds 3–8 an d 10–18 was determ in ed by 1H an d
13C NMR spectroscopy. Structural assign m en t of proton s an d carbon atom s
was ach ieved usin g correlated h om on uclear 2D-COSY, 2D-ROESY an d
h eteron uclear 1H,13C-2D-HSQC spectra; NMR param eters are sum m arized
in Tables I–III. Th e presen ce of 2,3-epoxy group in com poun ds 3–5 is m an i-
fested by upfield sh ifts of carbon atom s C-2 an d C-3 (δ 50–54) an d ch arac-
teristic vicin al couplin g J(2,3) ≈ 4 Hz. Th e presen ce of substituen ts –(CH2)3X
at C-4 is well docum en ted in 1H an d 13C NMR spectra. Th e fusion of th e
piperidin e rin g at C-3 an d C-4 in com poun ds 6–8 is proved by th e observed
upfield sh ifts of th ese carbon atom s (C-3 to δ ≈ 50–56; C-4 to δ ≈ 35–40).
Th e partial double-bon d ch aracter of th e tertiary am ide bon d in N-acetyl
derivative 7 leads to th e existen ce of two isom ers observed in th e NMR
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1,6-Anhydro-β-D-hexopyranoses
1433
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1434
Trtek et al.:
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1,6-Anhydro-β-D-hexopyranoses
1435
TABLE II
1H NMR couplin g con stan ts of com poun ds 3–8 an d 10–18
Com -
poun d
Solven t
1,2
2,3
3,4
4,5
5,6en
5,6ex
6en ,6ex
b
b
b
b
b
b
b
b
b
b
b
b
3a
4a
5a
6
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
3.2
3.2
3.2
1.8
1.8
3.9
0.4
0.5
0.5
5.8
5.3
≈0.8
≈0.8
3.9
3.9
≈0.8
b
9.3
(Z)-7
74%
10.0
≈1.5
0.9
0.9
4.7
4.3
5.2
5.0
5.0
4.7
7.5
7.5
(E)-7
26%
CDCl3
D2O
1.8
7.5
7.4
9.3
11.2
10.7
–
5.5
4.8
5.6
–
1.8
b
α-(Z)-8
49%
12.0
12.0
b
α-(E)-8
38%
D2O
CDCl3
10
2.1
2.1
1.0
5.4
8.6
11c
12d
13e
14
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
2.1
2.3
2.1
2.0
2.1
2.0
1.8
2.1
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
2.1
2.3
2.1
2.1
2.1
4.4
4.7
4.2
0.8
0.9
0.8
0.8
0.8
0
5.4
5.5
5.3
5.3
5.4
4.6
4.7
4.6
8.6
8.5
8.6
8.5
8.8
8.6
8.2
8.3
15
16
17f
(Z)-18g
0
0
80%
(E)-18h
CDCl3
2.1
–
–
4.0
0
4.7
8.5
20%
a
b
J(1,4) ≈ 0.5, J(2,4) = 0.6, J(3,5) = 1.4, J(1,6ex) ≈ J(1,6en ) ≈ 0.5; J value could n ot be deter-
c
d
m in ed; J(1,6ex) = 0.4, J(2,4) = 0.6, J(2,5) = 0.5; J(1,4) = 0.5, J(2,4) = 1.0, J(1,6ex) = 0.3,
J(2,5) = 0.3; J(1,5) = 0.5; J(4,6ex) = 1.2; J(4,6ex) = 1.3; J(4,6ex) = 1.1.
e
f
g
h
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1436
Trtek et al.:
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1,6-Anhydro-β-D-hexopyranoses
1437
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1438
Trtek et al.:
spectra. Th ey could be iden tified as (Z)- an d (E)-isom ers on th e basis of th e
observed NOE con tacts between m eth yl proton s of N-acetyl group an d th e
proton s of N–CH2 group (in (Z)-isom er; 74%) an d/or H-3 proton (in (E)-
isom er; 24%). Th e addition al NOE con tacts between H-2 an d two axial pro-
ton s of piperidin e rin g, observed in both isom ers, con firm th e orien tation
of piperidin e rin g (see Figs 1a an d 1b). Th e open in g of th e 1,6-an h ydride
rin g an d th e presen ce of N-acetyl group leads to th e observation of four
stereoisom ers (ratio 49:38:7:6) in th e NMR spectrum of com poun d 8 in D2O
solution . Two m ajor α-an om ers h ave an axial an om eric proton C(1)–H (as
in dicated by a large value of J(1,2) ≈ 7.5 Hz) an d (Z)- an d (E)-con figuration ,
respectively, as follows from th e NOE con tacts of N-acetyl group. Min or
β-an om ers con tain equatorial proton C(1)–H (sm all J(1,2) ≈ 3.5 Hz) an d (Z)-
an d (E)-con figuration , respectively. It is of in terest th at th e pyran rin g in
1
both m ajor isom ers adopts C4 con form ation (th e observed J(2,3) ≈ 11 Hz
in dicates diaxial orien tation of H-2 an d H-3). Th e NMR param eters of m i-
a
b
c
d
FIG. 1
Th e selected NOE con tacts (in dicated with arrows) observed in N-acetyl derivatives 7 an d 18:
a 7 (Z)-isom er; b 7 (E)-isom er; c 18 (Z)-isom er; d 18 (E)-isom er
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1,6-Anhydro-β-D-hexopyranoses
1439
n or β-an om ers are n ot given in Tables I–III sin ce th eir low population (ca. 7
an d 6%) does n ot allow extractin g com plete data sets.
Th e presen ce of th e quatern ary carbon atom C-3 in com poun ds 10–18
follows from 13C NMR spectra (a weak sign al with positive am plitude in
APT spectrum ) an d from th e absen ce of H-3 sign al in 1H NMR spectrum .
Th e presen ce of OH group at position C-3 is in dicated by ch em ical sh ifts of
carbon C-3 (δ ≈ 65.7–67.9). Th e th ree-carbon substiuen t at C-3 an d th e
tosyl groups at C-2 an d C-4 are m an ifested by ch aracteristic sign als in 1H
an d 13C NMR spectra. Oxolan e rin g closure leadin g to th e spiro com poun d
12 is in dicated by dram atic down field sh ift of C-3 (δ 77.00 in 12 versus
67.88 in 11) togeth er with n on equivalen ce of six –(CH2)3–O–C(3) proton s
in 12. Th e observed NOE con tacts of th e proton s of –C(3)–CH2– group in
th e oxolan e rin g with H-6en of th e 1,6-an h ydride bon d an d with proton s
H-2 an d H-4 of pyran ose rin g (Fig. 2) clearly dem on strate th e con figuration
of th e –(CH2)3–O– group at C-3 as well as th e 1C4 con form ation of th e
pyran ose rin g. Th ose NOE con tacts could n ot be observed in case of th e in -
verted con figuration at C-3 an d/or presen ce of th e B3,O con form ation of th e
pyran ose rin g. Th e piperidin e rin g in com poun ds 16–18 leads to an upfield
sh ift of C-4 (to δ ≈ 55–60) as th e result of th e replacem en t of oxygen with
n itrogen substituen t th at is also respon sible for an in crease of proton cou-
plin g J(4,5) from ≈2 Hz in 10–15 to ≈4 Hz in 16–18. Th e N-acetyl derivative
18 exists in solution again as a m ixture of (Z)- an d (E)-isom er in th e ratio
80:20 determ in ed from th e NOE con tacts of N-acetyl group. Th e addition al
NOE con tacts between H-6en an d two axial proton s of piperidin e rin g, ob-
served in both isom ers, con firm th e orien tation of th e piperidin e rin g (see
Figs 1c an d 1d). Th e observed decrease in vicin al couplin gs J(6en ,5) an d
J(6ex,5) (from ca. 0.8 an d 5.4 Hz in 10–15 to about 0 an d 4.5 Hz in 16–18)
FIG. 2
Th e observed NOE con tacts (in dicated with arrows) provin g th e structure of com poun d 12
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1440
Trtek et al.:
results probably from th e steric in teraction between th e piperidin e rin g an d
1,6-an h ydride bon d in 16–18.
Conformation of Compound 6 in Crystal
Th e crystal structure of com poun d 6 is sh own in Fig. 3. Th e five-m em bered
rin g adopts th e en velope con form ation EO2, th e pyran ose rin g h as a flat-
C3
ten ed ch air con form ation
con form ation
C
an d th e piperidin e rin g exists in th e ch air
O2
N1
C . Th e selected torsion an gles are given in Table IV.
C9
TABLE IV
Selected torsion an gles (in °) foun d in crystal structure of com poun d 6
Dioxolan e rin g
Pyran ose rin g
Piperidin e rin g
O1–C1–O2–C5
C1–O2–C5–C6
O2–C5–C6–O1
C5–C6–O1–C1
C6–O1–C1–O2
–43.8
44.9
–30.6
4.9
C1–C2–C3–C4
C2–C3–C4–C5
C3–C4–C5–O2
C4–C5–O2–C1
C5–O2–C1–C2
O2–C1–C2–C3
47.7
–46.2
60.4
C3–N1–C7–C8
N1–C7–C8–C9
C7–C8–C9–C4
C8–C9–C4–C3
C9–C4–C3–N1
C4–C3–N1–C7
–59.6
59.8
–57.2
51.8
–74.4
76.2
23.7
–49.5
54.3
–64.6
FIG. 3
A view on th e m olecule of 6 with atom n um berin g sch em e. Th e displacem en t ellipsoids are
17
drawn on 50% probability level (PLATON
)
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1,6-Anhydro-β-D-hexopyranoses
1441
EXPERIMENTAL
Th e m eltin g poin ts were determ in ed with a Boëtius m icro m eltin g-poin t apparatus an d are
un corrected. Optical rotation s were m easured with a polarim eter Autopol III (Rudolph
Research , Flan ders (NJ)) at 23–25 °C, [α]D values are given in 10–1 deg cm 2 g–1. NMR spectra
were m easured on Varian UNITY-500 an d/or Bruker AVANCE-500 apparatus (1H at 500 MHz,
13C at 125.7 MHz). Ch em ical sh ifts in ppm (δ-scale) were referen ced to tetram eth ylsilan e (in
1H NMR spectra) an d/or to th e solven t sign al (δ(CDCl3) 77.0 in 13C NMR spectra); couplin g
con stan ts (J) are given in Hz. ESI MS were m easured on an Esquire 3000 apparatus (Bruker).
Th in -layer ch rom atograph y (TLC) was perform ed on DC Alufolien plates (Merck, type 5554)
coated with Kieselgel 60 F254; detection was perform ed with 3% eth an olic solution of
an isaldeh yde acidified with con cen trated sulfuric acid, an d h eatin g. For preparative colum n
ch rom atograph y, silica gel Kieselgel 60 (Merck) was used. Solution s were dried with an -
h ydrous calcium ch loride an d were evaporated un der reduced pressure at tem peratures be-
low 40 °C. An alytical sam ples were dried over ph osph orus pen toxide at room tem perature
un der reduced pressure. For 1H an d 13C NMR data see Tables I–III.
1,6:2,3-Dian h ydro-4-deoxy-4-[3-(tosyloxy)propyl]-β-D-m an n opyran ose (3)
A solution of 1,6:2,3-dian h ydro-4-deoxy-4-(3-h ydroxypropyl)-β-D-m an n opyran ose5 (2) (2.2 g,
12 m m ol) in dry pyridin e (20 m l) was cooled to 0 °C an d tosyl ch loride (4.5 g, 24 m m ol) in
pyridin e (20 m l) was added. Th e m ixture was stirred at room tem perature for 2 h an d th en
poured in to ice-water (100 m l). Th e em ulsion was extracted with dich lorom eth an e (3 ×
30 m l). Com bin ed organ ic ph ases were dried an d evaporated. Yield 3.4 g (84%) of slowly
crystallizin g syrup 3, m .p. 81–83 °C (eth er–ligh t petroleum ), [α]D –18 (c 0.7, CHCl3). For
C
16H20O6S (340.4) calculated: 56.46% C, 5.92% H, 9.42% S; foun d: 56.57% C, 6.02% H,
9.37% S.
1,6:2,3-Dian h ydro-4-(3-azidopropyl)-4-deoxy-β-D-m an n opyran ose (4)
A m ixture of tosylate 3 (3.1 g, 9.1 m m ol) an d sodium azide (1.2 g, 18 m m ol) in an h ydrous
N,N-dim eth ylform am ide (15 m l) was h eated to 60 °C un der argon atm osph ere, wh ile stir-
rin g. Th e reaction was m on itored by TLC (toluen e–eth yl acetate 3:1; com plete con version
was observed after ca. 2 h ). After coolin g down , N,N-dim eth ylform am ide was evaporated
an d th e residue was extracted with eth er (30 m l). In soluble salts were filtered off, wash ed
with eth er (10 m l) an d th e filtrate was evaporated. Th e crude product was partially purified
on a silica gel colum n (70 g) in toluen e–eth yl acetate (4:1); yield 1.6 g (83%) of th e syrupy
azide derivative 4, [α]D –15 (c 0.6, CHCl3). For C9H13N3O3 calculated 211.1. ESI MS, m/z (%):
234.0 (100) [M + Na]+, 279.0 (46), 345.3 (91), 363.1 (30) [M of 3 + Na]+.
3-Am in o-1,6-an h ydro-3,4-dideoxy-3-N,4-C-(propan e-1,3-diyl)-β-D-altropyran ose (6)
Azide 4 (1.5 g, 7.1 m m ol) was h ydrogen ated in m eth an ol (20 m l) over 5% palladium on ac-
tivated carbon (100 m g) at atm osph eric pressure for 8 h . Th e catalyst was filtered off an d
th e filtrate con tain in g 4-(3-am in opropyl)-1,6:2,3-dian h ydro-4-deoxy-β-D-m an n opyran ose (5)
was refluxed for 4 h . Th e solven t was evaporated an d th e crude product was purified on a
sh ort silica gel colum n (15 g). Non polar im purities were eluted with eth yl acetate–m eth an ol
(10:1) an d th e product 6 was eluted with eth yl acetate–m eth an ol–20% am m on ia in m eth a-
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Trtek et al.:
n ol (15:3:1). It was crystallized from ethanol–ether, yield 840 m g (64%) of 6, m .p. 160–162 °C,
[α]D –178 (c 0.6, MeOH). For C9H15NO3 (185.2) calculated: 58.36% C, 8.16% H, 7.56% N;
foun d: 58.37% C, 8.26% H, 7.38% N.
Crystal data for 6: C9H15NO3, M = 185.22, orth orh om bic, P212121 (No. 19), a = 8.1500(2) Å,
b = 8.4880(2) Å, c = 12.8770(4) Å, V = 890.79(4) Å3, Z = 4, Dx = 1.381 Mg m –3. A yellow
crystal of dim en sion s 0.6 × 0.45 × 0.22 m m was m oun ted on glass capillary with epoxy glue
an d m easured at Non ius KappaCCD diffractom eter usin g m on och rom atized MoKα radiation
(λ = 0.71073 Å) at 150(2) K. An absorption was n eglected (µ = 0.103 m m –1); a total of 11 508
m easured reflection s in th e ran ge h = –10 to 10, k = –10 to 11, l = –16 to 16 (θm ax = 27.5°),
from wh ich 2042 were un ique (Rin t = 0.026) an d 1961 observed accordin g to th e I > 2σ(I)
criterion . Cell param eters from 1210 reflection s (θ = 1–27.5°). Th e structure was solved by
direct m eth ods (SIR92 13, Altom are, 1994) an d refin ed by full-m atrix least squares based on
F2 (SHELXL97 14). Th e h ydrogen atom s on carbon s were foun d on differen ce Fourier m ap,
were recalculated in to idealised position s an d fixed durin g refin em en t (ridin g m odel) with
assign ed tem perature factors Hiso(H) = 1.2Ueq(pivot atom ). Th e h ydrogen atom on N an d O
were foun d on differen ce Fourier m ap an d refin ed isotropically. Th e refin em en t con verged
(∆/σm ax = 0.000) to R = 0.029 for observed reflection s an d wR = 0.078, GOF = 1.061 for 126
param eters an d all 2042 reflection s. Th e fin al differen ce m ap displayed n o peaks of ch em ical
sign ifican ce (∆ρm ax = 0.223 e Å–3, ∆ρm in –0.173 e Å–3). Th e absolute structure was assign ed
by referen ce to kn own ch iral cen tre. (Flack param eter is –0.2(9).) CCDC 268301 con tain s th e
supplem en tary crystallograph ic data for th is paper. Th ese data can be obtain ed free of
ch arge via www.ccdc.cam .ac.uk/con ts/retrievin g.h tm l (or from th e Cam bridge Crystallo-
graph ic Data Cen tre, 12, Un ion Road, Cam bridge, CB2 1EZ, UK; fax: +44 1223 336033; or
deposit@ccdc.cam .ac.uk).
3-Acetam ido-1,6-an h ydro-3,4-dideoxy-3-N,4-C-(propan e-1,3-diyl)-β-D-altropyran ose (7) an d
3-Acetam ido-3,4-dideoxy-3-N,4-C-(propan e-1,3-diyl)-D-altropyran ose (8)
Com poun d 6 (80 m g, 0.40 m m ol) was dissolved in acetic an h ydride (1.0 m l), wh ile coolin g
to 0 °C, an d trifluoroacetic acid (100 µl, 1.3 m m ol) was added. Th e m ixture was kept at
room tem perature un der stirrin g for 2 days. Solven ts were evaporated at 30 °C. Syrupy m ate-
rial obtain ed was deacetylated in a solution of 0.2 M m eth an olic sodium m eth an olate (2 m l)
at room tem perature for 1 h . TLC (eth yl acetate-m eth an ol 10:1) sh owed th e presen ce of two
products. Th e m ixture was th en n eutralized with Dowex 50 (H+), th e resin was filtered off,
wash ed with m eth an ol an d com bin ed filtrates were evaporated. Th e residue was
ch rom atograph ed on a silica gel colum n (5 g). Com poun d 7 was eluted with eth yl acetate
an d com poun d 8 was eluted with eth yl acetate–m eth an ol (6:1).
Com poun d 7: Yield 45 m g (46%) of crystals, m .p. 190–191 °C (eth an ol–eth er), [α]D –49
(c 0.2, CHCl3). For C11H17NO4 (227.3) calculated: 58.14% C, 7.54% H, 6.16% N; foun d:
58.08% C, 7.55% H, 5.91% N.
Com poun d 8: Yield 25 m g (24%) of th e syrup. For C11H19NO5 calculated 245.1. ESI MS,
m/z (%): 250.0 (20), 268.1 (100) [M + Na]+.
3-C-Allyl-1,6-an h ydro-2,4-di-O-tosyl-β-D-allopyran ose (10)
A solution of 1,6-an h ydro-2,4-di-O-tosyl-β-D-ribo-h exopyran os-3-ulose (9)8 (4.0 g, 8.6 m m ol)
in dry THF (20 m l) was slowly added, wh ile stirrin g an d coolin g (–10 °C) to a solution of
allylm agn esium ch loride in THF (10 m l, 2 m ol/l, 20 m m ol). After 1 h , th e reaction m ixture
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1,6-Anhydro-β-D-hexopyranoses
1443
was warm ed to room tem perature an d stirred for addition al 1 h . Th e reaction was quen ch ed
carefully with 10% HCl (10 m l) un der coolin g (0 °C). Th e m ixture was separated between
eth er (40 m l) an d water (40 m l). Th e water ph ase was extracted with eth er (40 m l) again .
Com bin ed eth er extracts were dried an d evaporated. Th e crude product was crystallized
from eth er–ligh t petroleum , yield 2.8 g (64%) of th e allyl derivative 10, m .p. 127–128 °C,
[α]D –51 (c 0.7, CHCl3). For C23H26O9S2 (510.6) calculated: 54.10% C, 5.13% H, 12.56% S;
foun d: 54.22% C, 5.18% H, 12.42% S.
1,6-An h ydro-3-(3-h ydroxypropyl)-2,4-di-O-tosyl-β-D-allopyran ose (11)
A m ixture of BF3·Et2O (2.6 m l) an d bis(2-m eth oxyeth yl) eth er (5 m l) was added dropwise
un der argon atm osph ere durin g ca. 20 m in to a stirred suspen sion of sodium boroh ydride
(1.1 g) in bis-(2-m eth oxyeth yl) eth er (5 m l). Th e resultin g stream of diboran e15 was passed
th rough a stirred solution of 10 (2.5 g, 4.9 m m ol) in dry THF (20 m l). After com plete addi-
tion of th e BF3·Et2O solution , th e reaction m ixture was stirred for 1 h . Th e reaction was
quen ch ed cautiously un der coolin g (0 °C) with aqueous 3
M NaOH (55 m l) an d sub-
sequen tially with 30% H2O2 (55 m l). Th e m ixture was stirred at room tem perature for 1 h
an d th en extracted with ch loroform (2 × 30 m l). Com bin ed organ ic ph ases were wash ed
with saturated solution of Na2SO3 (50 m l), water (50 m l), an d th en were dried an d evapo-
rated. Th e residue was crystallized from eth an ol affordin g 2.0 g (77%) of diol 11, m .p.
152–154 °C, [α]D –33 (c 0.7, CHCl3). For C23H28O10S2 (528.6) calculated: 52.26% C, 5.34% H,
12.13% S; foun d: 51.87% C, 5.28% H, 11.96% S.
1,6-An h ydro-3-C,3-O-(propan e-1,3-diyl)-2,4-di-O-tosyl-β-D-allopyran ose (12)
A solution of th e com poun d 11 (1.0 g, 1.9 m m ol) in dry pyridin e (5 m l) was cooled to 0 °C
an d tosyl ch loride (760 m g, 4.0 m m ol) in pyridin e (5 m l) was added. Th e m ixture was
stirred at room tem perature for 2 h an d th en was poured in to ice-water (50 m l). Th e solid
m aterial precipitated overn igh t was wash ed with water, dried an d crystallized from aceton e,
yield 760 m g (79%) of 12, m .p. 196–199 °C (aceton e), [α]D –30 (c 0.8, CH3CN). For
C
23H26O9S2 (510.6) calculated: 54.10% C, 5.13% H, 12.56% S; foun d: 54.11% C, 5.11% H,
12.27% S. ESI MS, m/z (%): 533.2 (100) [M + Na]+, 549.1 (69) [M + K]+.
1,6-An h ydro-3-C-(3-azidopropyl)-2,4-di-O-tosyl-β-D-allopyran ose (13)
Com poun d 11 (2.0 g, 3.8 m m ol) an d triph en ylph osph in e (1.2 g, 4.6 m m ol) were dissolved
in THF (12 m l). To th is solution were added subsequen tly un der coolin g (0 °C): a) a dried
ben zen e solution of HN3 (4.5 m l), wh ich was prepared16 from a m ixture of NaN3 (1.0 g), wa-
ter (1 m l), ben zen e (6 m l) an d con cen trated sulfuric acid (0.4 m l) un der coolin g (0 °C);
b) diisopropyl diazen edicarboxylate (0.94 m l, 4.6 m m ol). Th e reaction m ixture was stirred at
room tem perature for 1 h , th en evaporated an d th e residue was ch rom atograph ed on a silica
gel colum n (100 g) in toluen e–aceton e (10:1). Yield 2.0 g (95%) of azide derivative 13, m .p.
129–130 °C (aceton e–eth er–ligh t petroleum ), [α]D –30 (c 0.6, CHCl3). For C23H27O9N3S2
(553.6) calculated: 49.90% C, 4.92% H, 7.59% N, 11.58% S; foun d: 49.64% C, 4.90% H,
7.44% N, 11.64% S.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1444
Trtek et al.:
3-C-(3-Am in opropyl)-1,6-an h ydro-2,4-di-O-tosyl-β-D-allopyran ose (14)
Azido com poun d 13 (2.0 g, 3.6 m m ol) was h ydrogen ated in a m ixture of ch loroform (10 m l),
m eth an ol (30 m l), acetic acid (1 m l) an d palladium on activated carbon (10%, 100 m g) for
48 h . Th e catalyst was filtered off an d solven ts were evaporated. Th e crude product was puri-
fied on a sh ort silica gel colum n (50 g) in ch loroform –m eth an ol–20% am m on ia in m eth an ol
(20:3:1). Yield 1.4 g (73%) of a syrupy am in e 14, [α]D –29 (c 0.7, CHCl3). For C23H29O9NS2
calculated 527.1. ESI MS, m/z (%): 528.1 (100) [M + H]+, 550.1 (70) [M + Na]+.
1,6-An h ydro-2,4-di-O-tosyl-3-C-[3-(tosylam in o)propyl]-β-D-allopyran ose (15)
To a solution of am in e 14 (3.5 g, 6.6 m m ol) in dry dich lorom eth an e (20 m l) an d trieth yl-
am in e (2.5 m l) was added tosyl ch loride (2.5 g, 13 m m ol) in dich lorom eth an e (20 m l) un der
coolin g (0 °C). Th e m ixture was stirred at 0 °C for 1 h an d th en poured in to ice-water (40 m l).
Dich lorom eth an e layer was separated an d th e water ph ase was extracted with dich loro-
m eth an e (20 m l) again . Com bin ed dich lorom eth an e solution s were dried an d evaporated.
Th e residue was ch rom atograph ed on a silica gel colum n (150 g) in toluen e–aceton e (10:1 →
4:1), yield 3.2 g of tosylam ide 15 (71%), m .p. 165–167 °C (eth an ol), [α]D –21 (c 0.7, CHCl3).
For C30H35NO11S3 (681.8) calculated: 52.85% C, 5.17% H, 2.05% N, 14.11% S; foun d:
52.59% C, 5.14% H, 1.90% N, 13.77% S.
1,6-An h ydro-4-deoxy-3-C,4-N-(propan e-1,3-diyl)-2-O-tosyl-4-(tosylam in o)-
β-D-gulopyran ose (16)
A m ixture of tritosyl derivative 15 (2.9 g, 4.3 m m ol) an d K2CO3 (1.8 g, 13 m m ol) in DMF
(50 m l) was h eated un der argon atm osph ere to 110 °C for 10 h , un til th e con version was
n early com plete (TLC, toluen e–aceton e 10:1). DMF was evaporated at 40 °C an d th e residue
was portition ed between water (30 m l) an d dich lorom eth an e (30 m l). Th e water ph ase was
extracted with dich lorom eth an e (20 m l) again . Com bin ed dich lorom eth an e extracts were
dried an d evaporated. Th e syrup th us obtain ed was ch om atograph ed on a silica gel colum n
(110 g) in toluen e–aceton e (20:1 → 10:1). Yield 1.5 g (69%) of th e syrupy tosyl am ide 16,
[α]D +61 (c 0.7, CHCl3). For C23H27NO8S2 calculated 509.1. ESI MS, m/z (%): 532.3 (100)
[M + Na]+.
4-Am in o-1,6-an h ydro-4-deoxy-3-C,4-N-(propan e-1,3-diyl)-β-D-gulopyran ose (17)
To a m ixture of th e sulfon am ide 16 (900 m g, 1.8 m m ol) an d Na2HPO4 (1.3 g, 9.1 m m ol ) in
dry m eth an ol (30 m l) was added 3% sodium am algam (6.7 g, 8.7 m m ol Na) at room tem per-
ature. Th e m ixture was h eated to reflux an d stirred un der argon atm osph ere. Th e sam e
am oun ts of am algam an d Na2HPO4 were added after 6 h an d th e m ixture was refluxed for
an oth er 6 h . Th e reaction was allowed to reach room tem perature, th e am algam was sepa-
rated an d th e m eth an olic suspen sion was filtered th rough celite. Th e filtrate was evaporated
an d th e residue was ch rom atograph ed on a silica gel colum n (12 g) in ch loroform –m eth an ol–
20% am m on ia in m eth an ol (20:1:1). Yield 230 m g (65%) of 17, m .p. 183–184 °C (eth an ol–
eth er), [α]D –14 (c 0.7, MeOH). For C9H15NO4 (201.2) calculated: 53.72% C, 7.51% H, 6.96% N;
foun d: 53.47% C, 7.48% H, 6.70% N.
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1,6-Anhydro-β-D-hexopyranoses
1445
Attem pt at Acetolysis of th e 1,6-An h ydride Bon d in 17:
4-Acetam ido-1,6-an h ydro-4-deoxy-3-C,4-N-(propan e-1,3-diyl)-β-D-gulopyran ose (18)
Com poun d 17 (50 m g, 0.25 m m ol) was dissolved in a m ixture of acetic an h ydride (0.5 m l)
an d acetic acid (50 µl), wh ile coolin g to 0 °C, an d trifluoroacetic acid (50 µl, 0.7 m m ol) was
added. Th e m ixture was kept at room tem perature un der stirrin g for 2 days. Solven ts were
evaporated at 30 °C. Th e syrupy m aterial th us obtain ed was deacetylated in a solution of
0.2 M m eth an olic sodium m eth an olate (2 m l) at room tem perature for 1 h . TLC (ch loroform –
m eth an ol 5:1) sh owed th e presen ce of a sin gle product. Th e m ixture was th en n eutralized
with Dowex 50 (H+), th e resin filtered off, wash ed with m eth an ol an d th e com bin ed filtrates
were evaporated. Th e residue was ch rom atograph ed on a silica gel colum n (3 g) in eth yl
acetate–m eth an ol (10:1). Yield 43 m g (71%) of syrupy acetam ide 18, [α]D +56 (c 0.5, CHCl3).
For C11H17NO5 calculated 243.1. ESI MS, m/z (%): 266.0 (100) [M + Na]+.
We thank Mgr M. Valášek for the measurement of mass spectra, Mgr B. Šperlichová for the mea-
surement of optical rotations and the Analytical Department of the Institute of Organic Chemistry and
Biochemistry of the Academy of Sciences of the Czech Republic for elementary analyses. This project
was supported by grant of the Ministry of Education, Youth and Sports of the Czech Republic MSM
1131 00001 and research project Z4 055 0506.
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