Synthesis of tricycles based on 1,6-anhydro-β-D-hexopyranoses fused with morpholine. 3,10,12-Trioxa-6-azatricyclo[7.2.1.02,7]dodecanes

Article abstract of DOI:10.1135/cccc20031295

The key step of the synthetic route was opening of the oxirane ring in 1,6:3,4-dianhydro-2-O-tosyl-β-D-galactopyranose (1) with 2-chloroethanol to give 1,6-anhydro4-O-(2-chloroethyl)-2-O-tosyl-β-D-glucopyranose (2), which was converted in four steps into

Full text of DOI:10.1135/cccc20031295

Synthesis of Tricycles
1295
SYNTHESIS OF TRICYCLES BASED ON 1,6-ANHYDRO-β-D-HEXO-
PYRANOSES FUSED WITH MORPHOLINE. 3,10,12-TRIOXA-6-AZA-
TRICYCLO[7.2.1.02,7]DODECANES
b
Tomáš TRTEKa1,*, Miloslav ČERNÝa2, Tomáš TRNKAa3, Miloš BUDĚŠÍNSKÝ and
c
Ivana CÍSAŘOVÁ
a
Department of Organic Chemistry, Charles University, Hlavova 2030, 128 40 Prague 2,
1
2
3
Czech Republic; e-mail: kkkrtekkk@email.cz, mila@natur.cuni.cz, trnka@natur.cuni.cz
Institute of Organic Chemistry and Biochemistry, 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
b
c
Received Jan uary 28, 2003
Accepted April 15, 2003
Dedicated to the memory of Professor Jaroslav Staněk.
Th e key step of th e syn th etic route was open in g of th e oxiran e rin g in 1,6:3,4-di-
an h ydro-2-O-tosyl-β-D-galactopyran ose (1) with 2-ch loroeth an ol to give 1,6-an h ydro-
4-O-(2-ch loroeth yl)-2-O-tosyl-β-D-glucopyran ose (2), wh ich was con verted in four steps in to
4-O-(2-am in oeth yl)-1,6:2,3-dian h ydro-β-D-m an n opyran ose (6). Th e latter com poun d un der-
wen t in tram olecular cyclisation to afford th e fused m orph olin e derivative 3-am in o-
1,6-an h ydro-3-deoxy-3-N,4-O-eth ylen e-β-D-altropyran ose (7) wh ich gave th e correspon din g
quatern ary am m on ium salt 11 by N-m eth ylation . Acid cleavage of th e 1,6-an h ydro bon d in
7 gave 3-acetam ido-3-deoxy-3-N,4-O-eth ylen e-D-altropyran ose (9).
Keyw ord s: Carboh ydrates; Heterocycles; 1,6-An h ydrosugars; Morph olin es; Am in o sugars;
Oxiran es; Epoxides; Cyclization s; X-ray diffraction ; Con form ation an alysis.
Morph olin e derivatives are widely used as ph arm aceuticals with a broad
spectrum of biological effects. In th ese com poun ds, m orph olin e rin g is fre-
quen tly presen t as a N-substituted term in al group1. On th e oth er h an d,
C-substituted m orph olin es also exh ibit biological activity as follows from
recen t studies2, for exam ple, on h ypoch olesterom ic an d h ypolipidem ic ac-
tivity3.
A search for n ew biologically active com poun ds prom ted us to explore
th is field. Com m on requirem en ts for ch iral purity of n ew com poun ds
turn ed our atten tion to th e use of carboh ydrates, particularly 1,6-an h ydro-
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pyran oses, as startin g m aterials. Bein g ch iral, th ey are used to advan tage in
stereoselective syn th eses of n atural com poun ds4, th eir an alogs5,6, an d poly-
m ers7.
In th is paper, we describe th e syn th esis of th e am in o sugars 7–11 con -
tain in g th e m orph olin e rin g, fused with a carboh ydrate skeleton . For th eir
syn th esis, we used reaction s of dian h ydro sugars8 (sugar epoxides). Open -
in g of th e oxiran e rin g in th ese rigid system s proceeds trans-diaxially, af-
fordin g en an tiom erically an d diastereom erically pure com poun ds.
As a startin g com poun d for th e syn th esis (Sch em e 1) of m orph olin e sugar
derivatives we ch ose 1,6:3,4-dian h ydro-2-O-tosyl-β-D-galactopyran ose (1),
readily accessible in two steps from 1,6-an h ydro-β-D-glucopyran ose9. Its
oxiran e rin g was cleaved with 2-ch loroeth an ol un der catalysis with boron
trifluoride in refluxin g dich lorom eth an e to give th e ch loroeth yl derivative
2 in 87% yield. Th e reaction proceeded with h igh regioselectivity, as with
oth er n ucleoph iles8,10. After acetylation of 2, th e ch lorin e atom in 3 was re-
O
O
OH
O
(i)
O
O
O
OTs
OTs
Cl
1
2
(ii)
O
O
O
OAc
O
(v)
O
O
O
OTs
H2N
X
6
(vi)
3, X = Cl
(iii)
4, X = N3
O
(iv)
(ii)
5a, X = NH2
5b, X = NHAc
O
OH
HN
O
7
(i) ClCH2CH2OH, BF3·Et2O, CH2Cl2, 40 oC; (ii) Ac2O, pyridine, r.t.; (iii) NaN3, DMF,
90 oC; (iv) H2, Pd/C, EtOH, r.t.; (v) MeONa, MeOH, r.t.; (vi) DBU, BuOH, 120 o
C
SCHEME 1
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Synthesis of Tricycles
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placed by th e azide group. Th is substitution was carried out in N,N-di-
m eth ylform am ide with sodium azide in alm ost 90% yield, givin g th e
azidoeth yl derivative 4, wh ich was th en h ydrogen ated over palladium cata-
lyst in alm ost quan titative yield. Treatm en t of th e resultin g am in e 5a with
m eth an olic sodium m eth oxide at room tem perature afforded th e am in o
epoxide 6. Base-catalysed in tram olecular open in g of th e epoxide rin g by
th e am in o group in com poun d 6 resulted in th e form ation of 3-am in o-
1,6-an h ydro-3-deoxy-3-N,4-O-eth ylen e-β-D-altropyran ose (7). Wh ereas n u-
cleoph ilic bases (NaOH, t-BuOK) caused partial solvolysis of th e oxiran e
rin g (cf. ref.11), usin g 1,8-diazabicyclo[5.4.0]un dec-7-en e (DBU) as a n on -
n ucleoph ilic base circum ven ted th ese difficulties to give 7 in 85% yield.
N,O-Diacetate 8a was prepared for X-ray an alysis (Fig. 1) by acetylation of 7
in a m ixture of acetic an h ydride an d sodium acetate.
Hydrolysis of th e 1,6-an h ydro bon d in tricyclic com poun d 7 with aque-
ous h ydroch loric acid failed because th e equilibrium between com poun d 7
an d th e correspon din g reducin g sugar is com pletely sh ifted to 7. Th is was
verified by con version of pure com poun ds 8a an d 9 in to 7 in a h ot aqueous
15% solution of HCl an d dem on strated by TLC. Neverth eless, acetolysis in
th e m ixture of trifluoroacetic acid an d acetic an h ydride at room tem perature
followed by Zem plén deacetylation gave th e reducin g sugar 9 (Sch em e 2).
O
HOH2C
OH
O
(i), (ii)
O
O
OH
OH
NAc
HN
O
7
(iii)
9
(v)
O
O
O
O
(iv)
O
CH3
OR2
O
OH
OH
+N
N
N
O
O
R1
O
CH3
CH3
8a, R1 = R2 = Ac
10
11
(ii)
8b, R1 = Ac, R2 = H
(vi)
8c, R1 = Ac, R2 = Ts
(i) CF3COOH, Ac2O, r.t.; (ii) MeONa, MeOH, r.t.; (iii) CH2O, HCOOH, 80 oC;
(iv) MeI, THF, r.t.; (v) Ac2O, AcONa, 70 oC; (vi) TsCl, pyridine, r.t.
SCHEME 2
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Quatern ary am m on ium salt 11 was prepared as a poten tial acetylch olin e
esterase in h ibitor. Direct N-m eth ylation of am in e 7 with m eth yl iodide in
th e presen ce of KHCO3 was com plicated by isolation of th e am m on ium salt
from th e reaction m ixture. Th at is wh y we decided to prepare 11 by partial
N-m eth ylation of am in o com poun d 7 usin g th e Esch weiler–Clark proce-
dure, followed by N-m eth ylation of th e resultin g N-m eth yl derivative 10
with m eth yl iodide in tetrah ydrofuran at room tem perature.
NMR AND X-RAY DISCUSSION
Th e structure of com poun ds 2, 4, 5b, 6, 7, 8a, 8b, 8c, 10, 11 was deter-
1
m in ed by H 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
an d h eteron uclear 1H, 13C-2D-HMQC spectra. Th e lon g-ran ge couplin gs,
typical of com poun ds with D-gluco con figuration 2, 4, 5 (m ain ly of proton
H-1) were iden tified with selective h om odecouplin g experim en ts. In com -
poun d 2, th e h igh er observed values of couplin g con stan ts J(2,3) = 3.7 Hz
an d J(3,4) = 4.0 Hz (in com parison with typical lower values J(2,3) ≈ 1.8 Hz
an d J(3,4) ≈ 1.8 Hz foun d in 4, 5b) can be explain ed eith er by flatten in g of
th e pyran ose rin g, an d/or a certain am oun t of th e boat form in ch air-boat
equilibrium of com poun d 2.
Th e presen ce of th e oxiran e rin g in D-manno-com poun d 6 m an ifests itself
by upfield sh ifts of proton s an d carbon atom s in position s 2 an d 3 (δ(H)
3.46 an d 3.19; δ(C) 54.35 an d 47.66) an d a ch aracteristic J-value of
cis-oxiran e proton s (J(2,3) = 3.8 Hz). Also oth er proton couplin g con stan ts
(J(1,2) = 3.2; J(3,4) < 0.5, J(4,5) = 1.1 Hz) are in agreem en t with th e D-manno
con figuration .
Th e D-altro con figuration of tricyclic com poun ds 7, 8a, 8b, 8c, 10, 11 was
proved by a large value of J(2,3) ≈ 9 Hz (indicating a trans-diaxial arrangem ent
of H-2, H-3) an d low J(3,4) ≈ 4 Hz of gauche-orien ted H-3 an d H-4. Th e pres-
en ce of n itrogen substituen t in stead of oxygen in position 3 (eviden ced by
upfield sh ifts of carbon C-3 to δ 46–60 in com poun ds 7, 8a, 8b) also leads
to an in crease in both of th e above m en tion ed vicin al couplin gs of H-3.
Th e D-altro con figuration of com poun d 7 is furth er supported by a h igh
n egative value of optical rotation ([α]D –140.5). Th e m orph olin e rin g fused
in position 3,4 adopts a ch air con form ation as it is in dicated by vicin al cou-
plin gs in th e O-CH2-CH2-N fragm en t (see Table II) an d a lon g-ran ge cou-
plin g (ca 1 Hz) of proton s in th e approxim ate byplan ar four-bon d fragm en t
H(eq)-C-N-C(3)-H. Th e partial double-bon d ch aracter of th e tertiary am ide
bon d in N-acetyl derivatives 8a, 8b an d 8c leads to th e existen ce of two iso-
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Synthesis of Tricycles
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m ers observed in th eir NMR spectra. Th ey could be assign ed (Z)- an d
(E)-isom er on th e basis of th e observed NOE con tacts between m eth yl pro-
ton s of N-acetyl group an d th e equatorial h ydrogen of N-CH2 group (in
(Z)-isom er) an d/or H-3 proton (in (E)-isom er), in accordan ce with a sh ort
distan ce (ca 2.5 Å) of th e correspon din g proton s in calculated en ergy m in i-
m ized structures. In all cases, th e population of (Z)-isom er prevails (55% in
8a, 69% in 8b an d 61% in 8c) in agreem en t with th e lower en ergy calcu-
lated for (Z)-isom er usin g th e MM+ m eth od (HYPERCHEM program ). It is
in terestin g th at also X-ray an alysis of diacetate 8a sh owed th e presen ce of
(E)- an d (Z)-isom ers in th e 1:1 ratio (see Figs 1a an d 1b). Bon d distan ces an d
an gles are un exception al, witn essin g electron delocalisation in N–C=O
m oiety (N–CAc bein g 0.1 Å sh orter th an th e rem ain in g two N–C bon ds –
see Table I) as well as a great sim ilarity of two isom ers. With th e exception
of orien tation of N-acetyl m oiety (torsion an gles C*7–N*6–C*61–O*62 are
9.4(2) an d –174.1(2)° for (Z)- an d (E)-form , respectively) th ey differ sligh tly
in orien tation of th e secon d acetyl plan e, because of steric requirem en ts of
th e m eth yl group of th e (E)-isom er (dih edral an gles between least-squares
plan es defin ed by C*61, N*6, O*62, C*63 an d C*82, O*81, O*83, C*84 are
36.2(1) an d 49.8(1)° for (Z)- (* = 1) an d (E)-isom er (* = 2), respectively).
NMR spectra of com poun d 9 sh owed th e presen ce of four species in solu-
tion obviously due to th e equilibrium population of α- an d β-an om ers,
each of th em existin g as a m ixture of (E)- an d (Z)-isom ers of th e tertiary
acetam ide groupin g. Th is is supported by th e sign als of an om eric proton s –
e.g., in com poun d 9, two sign als at δ 5.07 an d 5.03 sh ow large J(1,2) = 6.5
an d 7.4 Hz in accordan ce with a trans-diaxial orien tation of H-1, H-2 in α-
an om ers an d two addition al sign als at δ 5.35 an d 5.33 with a sm all J(1,2) =
3.6 Hz in dicatin g gauche-orien tation of H-1, H-2 in β-an om ers. Com plete
structure assign m en t of all proton s or carbon s in 9 is extrem ely difficult.
In con clusion , n ew en an tiom erically pure m orph olin e derivatives 7–11
were prepared usin g regio- an d stereoselective reaction s of dian h ydro sugars
obtain ed from 1,6-an h ydro-β-D-glucopyran ose. Th e syn th etic route de-
TABLE I
Selected bon d len gth s (in Å) for (Z)- an d (E)-isom ers of 8a
N16–C15
1.463(2)
1.359(2)
1.464(2)
1.232(2)
N26–C25
1.463(2)
1.368(2)
1.464(2)
1.230(2)
N16–C161
N16–C17
N26–C261
N26–C27
C161–O162
C261–O262
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Trtek et al.:
a
O110
C19
C111
O112
O181
C11
C18
C184
O162
C12
C17
C182
O183
C161
O13
N16
C163
C14
C15
b
O210
C211
O212
C29
C28
C21
C22
O281
C284
C27
C263
C282
O23
N26
O283
C261
C24
C25
O262
FIG. 1
View of (Z)-isom er (a) an d (E)-isom er (b) of 8a. Th e th erm al ellipsoids are drawn on 50% prob-
12
ability level (PLATON
)
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Synthesis of Tricycles
1301
scribed h ere allows an easy access to som e oth er ch iral h eterocycles of po-
ten tial biological activity.
EXPERIMENTAL
Meltin g poin ts were determ in ed with a Boetius 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 Re-
search , 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 apparatus (1H at 500, 13C at 125.7 MHz) in CDCl3 or
D2O. Ch em ical sh ifts (in ppm , δ-scale) were referen ced to tetram eth ylsilan e as in tern al stan -
dard; couplin g con stan ts (J) are given in Hz. Th in -layer ch rom atograph y (TLC) was per-
form 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 sul-
furic acid, an d by 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 th en evapo-
rated un der reduced pressure at tem peratures below 40 °C. An alytical sam ples were dried
over ph osph orus pen toxide at room tem perature un der reduced pressure.
1,6-An h ydro-4-O-(2-ch loroeth yl)-2-O-tosyl-β-D-glucopyran ose (2)
To a solution of th e tosylepoxide 1 (2.0 g, 6.7 m m ol) in an h ydrous dich lorom eth an e (20 m l)
boron trifluoride eth erate (1.0 m l, 7.9 m m ol) an d 2-ch loroeth an ol (2.2 m l, 33 m m ol) were
added. Th e m ixture was refluxed for 4 h . Th e reaction course was m on itored by TLC (eth yl
acetate–toluen e 1:2). Th e dich lorom eth an e solution was wash ed with a saturated solution of
sodium h ydrogen carbon ate (2 × 20 m l) an d with water (20 m l). Com bin ed organ ic extracts
were dried, dich lorom eth an e an d 2-ch loroeth an ol were evaporated to obtain 2.2 g (87%) of 2,
m.p. 67–68 °C (ethanol–ether–light petroleum), [α]D –39.0 (c 0.25, CHCl3). For 1H and 13C NMR
data, see Tables II–IV. For C15H19ClO7S (378.8) calculated: 47.57% C, 5.06% H, 8.46% S;
foun d: 47.68% C, 5.16% H, 8.58% S.
3-O-Acetyl-1,6-an h ydro-4-O-(2-ch loroeth yl)-2-O-tosyl-β-D-glucopyran ose (3)
Ch loroeth yl derivative 2 (1.4 g, 3.7 m m ol) was dissolved in an h ydrous pyridin e (4.0 m l), th e
solution was cooled to 0 °C an d acetic an h ydride (1.1 m l, 9.0 m m ol) was added dropwise.
Th e solution was stirred at room tem perature overn igh t an d th en poured in to ice-water
(30 m l) wh ile stirrin g. Th e resultin g precipitate was filtered off, wash ed with water (30 m l)
an d dried to give 1.5 g (98%) of 3, m .p. 111–112 °C (aceton e–eth er–ligh t petroleum ), [α]D
–24.8 (c 0.20, CHCl3). For C17H21ClO8S (420.9) calculated: 48.52% C, 5.03% H, 7.62% S;
foun d: 48.37% C, 5.13% H, 7.41% S.
3-O-Acetyl-1,6-an h ydro-4-O-(2-azidoeth yl)-2-O-tosyl-β-D-glucopyran ose (4)
Com poun d 3 (1.4 g, 3.7 m m ol) an d sodium azide (470 m g, 6.8 m m ol) were dissolved in an -
h ydrous N,N-dim eth ylform am ide (5.0 m l) an d th e m ixture was h eated to 90 °C for 3 h un -
der argon atm osph ere, wh ile stirrin g. After evaporation of N,N-dim eth ylform am ide, water
(30 m l) was added to th e residue. Th e in soluble product was filtered off an d recrystallized
from aceton e–eth er–ligh t petroleum affordin g 1.2 g (89%) of azide derivative 4, m .p.
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Synthesis of Tricycles
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TABLE IV
13C NMR data (in ppm , δ-scale) of com poun ds 2, 4–8, 10 (in CDCl3) an d 11 (in D2O)
Com p. C-1 C-2 C-3 C-4 C-5 C-6 Oth er carbon s
2
4
99.98 79.46 70.39 80.51 75.26 66.60 OCH2CH2Cl: 70.39, 42.96
OTos: 145.44, 132.94, 130.02(2),
127.97(2), 21.68
99.02 74.14 68.50 76.47 74.21 65.31 OCH2CH2N: 68.57, 50.63
OAc: 169.11, 20.85
OTos: 145.33, 133.24, 129.93(2),
127.97(2), 21.66
5b
98.84 74.22 68.84 75.57 74.04 65.23 OCH2CH2N: 68.73, 39.20
NAc: 169.06, 23.15
OAc: 169.06, 20.82
OTos: 145.54, 132.98, 130.05(2),
127.90(2), 21.67
6
7
97.59 54.35 47.66 75.05 71.44 65.78 OCH2CH2N: 72.67, 41.90
102.04 67.31 53.04 74.19 76.05 65.79 OCH2CH2N: 67.53, 39.44
(Z)-8a 100.22 69.13 47.11 74.48 75.66 65.85 OCH2CH2N: 66.60, 42.14
NAc: 171.06, 21.58
OAc: 169.54, 21.04
(E)-8a
99.64 69.78 51.93 74.48 75.62 66.07 OCH2CH2N: 66.94, 36.64
NAc: 171.06, 20.90
OAc: 170.04, 20.75
(Z)-8b 102.08 69.96 49.84 74.62 75.41 65.80 OCH2CH2N: 66.46, 42.25
NAc: 171.06, 21.56
(E)-8b 102.14 68.42 55.19 74.30 75.61 65.90 OCH2CH2N: 66.88, 36.86
NAc: 171.06, 21.56
(Z)-8c
99.91 75.20 51.94 74.82 75.51 66.13 OCH2CH2N: 66.88, 35.88
NAc: 169.23, 21.65
OTos: 145.64, 133.31, 130.21(2),
128.03(2), 21.65
(E)-8c
99.96 75.56 46.11 74.79 75.56 65.94 OCH2CH2N: 66.70, 41.85
OAc: 169.23, 21.14
OTos: 145.06, 132.16, 129.85(2),
127.91(2), 21.69
10
11
102.00 66.95 59.95 73.12 75.93 65.51 OCH2CH2N: 65.47, 47.68
NMe: 44.34
104.02 68.80 70.91 72.30 78.44 67.43 OCH2CH2N: 63.38, 60.28
NMe2: 59.12, 53.58
Ratio of (Z)- an d (E)-isom ers: 55% (Z)-8a, 45% (E)-8a, 69% (Z)-8b, 31% (E)-8b, 61% (Z)-8c,
39% (E)-8c.
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Synthesis of Tricycles
1305
103–104 °C, [α]D –30.2 (c 0.24, CHCl3). For 1H an d 13C NMR data, see Tables II–IV. For
17H21N3O8S (427.4) calculated: 47.77% C, 4.95% H, 9.83% N, 7.50% S; foun d: 47.91% C,
C
5.13% H, 9.61% N, 7.27% S.
3-O-Acetyl-4-O-(2-am in oeth yl)-1,6-an h ydro-2-O-tosyl-β-D-glucopyran ose (5a) an d
4-O-(2-Acetam idoeth yl)-3-O-acetyl-1,6-an h ydro-2-O-tosyl-β-D-glucopyran ose (5b)
Azide derivative 4 (1.2 g, 3.1 m m ol) was h ydrogen ated in eth an ol (50 m l) over Pd/C (60 m g,
5%) at atm osph eric pressure for 24 h . Th e catalyst was rem oved by filtration , wash ed with
eth an ol, an d com bin ed filtrates were evaporated. Th e residue was dissolved in water (15 m l),
an d n eutralized with 10% h ydroch loric acid to pH ≈ 6. Th e aqueous solution was extracted
with dich lorom eth an e (2 × 10 m l) an d organ ic extracts were wash ed with water (5 m l)
again . Com bin ed aqueous ph ases were evaporated an d codistilled with toluen e (3 × 10 m l)
to give 1.3 g of syrupy 5a wh ich was used with out furth er purification .
To a solution of am in e derivative 5a (100 m g, 0.25 m m ol) in an h ydrous pyridin e (1.0 m l)
cooled to 0 °C, acetic an h ydride (66 µl, 0.70 m m ol) was added wh ile stirrin g. Th e m ixture
was set aside at room tem perature overn igh t. Th en ice-water (8.0 m l) was added, an d th e so-
lution was extracted with dich lorom eth an e (3 × 4 m l). Com bin ed organ ic ph ases were dried
an d evaporated. Ch rom atograph y of th e residue on a silica gel colum n (5 g) in m eth an ol–
ch loroform (1:20) afforded 88 m g (79%) of syrup 5b, [α]D –38.0 (c 0.28, CHCl3). For 1H an d
13C NMR data, see Tables II–IV.
4-O-(2-Am in oeth yl)-1,6:2,3-dian h ydro-β-D-m an n opyran ose (6)
Com poun d 5a (1.2 g, 2.6 m m ol) was dissolved, wh ile stirrin g, in 0.5 M m eth an olic sodium
m eth oxide (11 m l) an d th e solution was set aside at room tem perature overn igh t. Th en th e
m ixture was n eutralized with acetic acid to pH ≈ 7. After evaporation of th e solven t, m eth a-
n ol was replaced with dich lorom eth an e (5 m l). In soluble salts were filtered off an d wash ed
with dich lorom eth an e (1 m l). Th e filtrate was con cen trated an d purified on a sh ort silica gel
colum n (12 g) in eth yl acetate–m eth an ol (3:1) to obtain 460 m g (94%) of syrup 6, [α]D –31.5
(c 0.25, CHCl3). For 1H an d 13C NMR data, see Tables II–IV.
3-Am in o-1,6-an h ydro-3-deoxy-3-N,4-O-eth ylen e-β-D-altropyran ose (7)
A solution of am in oepoxide 6 (460 m g, 2.4 m m ol) an d 1,8-diazabicyclo[5.4.0]un dec-7-en
(0.4 m l, 2.7 m m ol) in butan -1-ol (14 m l) was refluxed for 2 h . Th e solven t was evaporated
an d residue was ch rom atograph ed on a silica gel colum n (25 g) in m eth an ol–eth yl acetate
(1:3) to give 390 m g (85%) of syrupy com poun d 7, [α]D –140.5 (c 0.16, MeOH). For 1H an d
13C NMR data, see Tables II–IV. EI HRMS, m/z: calculated for C8H13NO4 187.084458; foun d
187.085928 (M+).
3-Acetam ido-2-O-acetyl-1,6-an h ydro-3-deoxy-3-N,4-O-eth ylen e-β-D-altropyran ose (8a)
Am in e derivative 7 (280 m g, 1.4 m m ol) was dissolved in a suspen sion of an h ydrous sodium
acetate (400 m g, 4.9 m m ol) in acetic an h ydride (1.0 m l). Th e m ixture was h eated to 70 °C
for 30 m in , th en cooled down an d a saturated solution of sodium h ydrogen carbon ate (10 m l)
was added in several portion s. After decom position of acetic an h ydride, th e m ixture was ex-
tracted with dich lorom eth an e (3 × 5 m l). Com bin ed organ ic layers were dried an d evapo-
Collect. Czech. Chem. Commun. (Vol. 68) (2003)

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Trtek et al.:
rated to give 390 m g (96%) of crystallin e 8a , m .p. 142–144 °C (eth an ol–eth er–ligh t
petroleum ), [α]D –23 (c 0.18, CHCl3). For 1H an d 13C NMR data, see Tables II–IV. For
C
12H17NO6 (271.3) calculated: 53.13% C, 6.32% H, 5.16% N; foun d: 53.13% C, 6.49% H,
5.05% N.
Crystal Structure An alysis of Com poun d 8a
A colourless crystal of dim en sion s 0.4 × 0.28 × 0.25 m m is triclin ic, space group P1,
C12H17NO6, M = 271.27, a = 8.2590(3) Å, b = 8.3350(2) Å, c = 10.6890(4) Å, α = 69.189(2)°,
β = 70.444(2)°, γ = 72.717(2)°, V = 634.74(4) Å3, Z = 2, Dx = 1.419 Mg m –3
.
All data were collected on a 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 = 0.114 m m –1);
a total of 8298 m easured reflection s in th e ran ge h = –10 to 10, k = –9 to 10, l = –13 to 11
(θm ax = 27.5°), from wh ich 4446 were un ique (Rin t = 0.033) an d 4228 observed accordin g to
th e I > 2σ(I) criterion . Cell param eters from 5074 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 were foun d on differen ce Fourier m ap an d
refin ed isotropically except th ose of m eth yl, wh ich 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) = 1.5 Ueq
(pivot atom ). Th e refin em en t con verged (∆/σm ax = 0.001) to R = 0.029 for observed reflec-
tion s an d wR = 0.068, GOF = 1.064 for 435 param eters an d all 4443 reflection s. Th e fin al
difference m ap displayed no peaks of chem ical significance (∆ρm ax = 0.156, ∆ρm in = –0.202 e Å–3).
Th e absolute structure was assign ed by referen ce to th e kn own ch iral cen tre. (Flack param e-
ter = 0.4(5).) CCDC 200816 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 Crystallograph 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-deoxy-3-N,4-O-eth ylen e-β-D-altropyran ose (8b)
A solution of diacetate 8a (300 m g, 1.31 m m ol) in 0.1 M sodium m eth an olate (6 m l) was
stirred at room tem perature for 1 h . 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 th e com bin ed filtrates were evaporated
to give 250 m g (98%) of crystallin e 8b, m .p. 195–197 °C (eth an ol–eth er), [α]D –38.8 (c 0.20,
CHCl3). For 1H an d 13C NMR data, see Tables II–IV. For C10H15NO5 (229.2) calculated:
52.40% C, 6.60% H, 6.11% N; foun d: 52.11% C, 6.78% H, 6.15% N.
3-Acetam ido-1,6-an h ydro-3-deoxy-3-N,4-O-eth ylen e-2-O-tosyl-β-D-altropyran ose (8c)
Com poun d 8b (180 m g, 0.79 m m ol) was dissolved in an h ydrous pyridin e (2.0 m l) an d tosyl
ch loride (225 m g, 1.18 m m ol) was added wh ile stirrin g. Th e reaction m ixture was set aside
at room tem perature overn igh t an d th en poured in to water (15 m l). Crystallin e tosylate was
filtered off, wash ed with water (10 m l) an d dried to give 255 m g (85%) of 8c, m .p. 183–
185 °C (aceton e–eth er–ligh t petroleum ), [α]D –36.6 (c 0.34, CHCl3). For 1H an d 13C NMR
data, see Tables II–IV. For C17H21NO7S (383.4) calculated: 53.25% C, 5.52% H, 3.65% N,
8.36% S; foun d: 53.63% C, 5.73% H, 3.77% N, 8.40% S.
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Synthesis of Tricycles
1307
3-Acetam ido-3-deoxy-3-N,4-O-eth ylen e-D-altropyran ose (9)
To a solution of diacetate 8a (100 m g, 0.37 m m ol) in acetic an h ydride (3.3 m l) was added
trifluoroacetic acid (0.33 m l, 4.3 m m ol) an d th e m ixture was stirred overn igh t. Th e solven ts
were rem oved in vacuo an d th e residue was separated between a saturated solution of so-
dium h ydrogen carbon ate (2 m l) an d ch loroform (2 m l). Th e aqueous layer was th en ex-
tracted by m ean s of ch loroform (2 × 2 m l). Com bin ed organ ic layers were dried an d
evaporated. Th e crude product th us obtain ed was deacetylated in a solution of 0.1
M
m eth an olic sodium m eth an olate (2.5 m l) at room tem perature for 2 h . 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
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 (4:1) to give 55 m g (60%) of 9, [α]D +26.3 (c 0.24,
MeOH). FAB MS, m/z: calculated for C8H16NO6 247.2; foun d 270.1 [M + Na]+.
1,6-An h ydro-3-deoxy-3-N,4-O-eth ylen e-3-m eth ylam in o-β-D-altropyran ose (10)
Com poun d 7 (380 m g, 2.0 m m ol) was dissolved in 85% form ic acid (0.15 m l, 3.3 m m ol)
an d a solution of 35% form aldeh yde (0.23 m l, 3.1 m m ol) was added. Th e m ixture was
h eated to 80 °C overn igh t. After coolin g down , th e solution was acidified with 6 M h ydro-
ch loric acid (0.5 m l) an d extracted with ch loroform (2 × 1 m l). Evaporation of com bin ed ex-
tracts afforded 5 m g of a syrup. Aqueous layer was alkalin ized with a 20% water solution of
NaOH an d set aside at room tem perature for 30 m in . Th e reaction m ixture was th en ex-
tracted with ch loroform (6 × 1 m l). Com bin ed ch loroform extracts were dried an d evapo-
rated to give 280 m g (68%) of 10, m .p. 113–115 °C (eth yl acetate–eth er–ligh t petroleum ),
[α]D –140.9 (c 0.26, CHCl3). For 1H an d 13C NMR data, see Tables II–IV. For C9H15NO4
(201.2) calculated: 53.72% C, 7.51% H, 6.96% N; foun d: 53.37% C, 7.74% H, 6.76% N.
1,6-An h ydro-3-deoxy-3-O,4-N-eth ylen e-3-(N,N-dim eth ylam m on io)-β-D-altropyran ose
Iodide (Altern ative Nam e (1R,2S,7S,8S,9R)-8-Hydroxy-6,6-dim eth yl-3,10,12-trioxa-
6-azon iatricyclo[7.2.1.02,7]dodecan e Iodide) (11)
Th e crude product of N-m eth ylation 10 (280 m g, 1.4 m m ol) was dissolved in tetrah ydro-
furan (3 m l), m eth yl iodide (300 µl, 4.8 m m ol) was added an d th e m ixture was kept at room
tem perature for 24 h . Precipitated product was filtered off an d wash ed with tetrah ydrofuran
(2 m l) to give 440 m g (92%) of 11, m .p. 276–277 °C (decom p., eth an ol), [α]D –74.4 (c 0.17,
MeOH). For 1H an d 13C NMR data, see Tables II–IV. For C10H18INO4 (343.2) calculated:
35.00% C, 5.29% H, 4.08% N; foun d: 34.74% C, 5.38% H, 3.83% N.
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