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2,5-disubstituted pyrrolidines from D-mannitol-derived bis-aziridines
TetruhedrcmLenas. Vol. 35. No. 8. pp. 1201-1204.1994 Elswier Sciarr IA RintedinGmatBritain 0040-4039194 56.00+0.00
0040-4039(94)EOO15-P
2,SDisubstituted
Juliette
Pyrrolidines
from
Bis- Aziridines
Fitremann,
Annie Durhult
D-Mannitol-Derived
*, Jean-Claude
Depezay
Absburcl : Concise syntheses of 3,4-dihy&oxy-2,Sdisubstituted
pyrrolidines have been achieved starting from Dmannitol-detivedjkzibk L-Id0 bis-aziridkes. Nuckophilic ring opening of the N-Boc and the N-Cbz activated bisasiridines by phenylthiolate and azide ions has beenstudied ; the reaction can be oriented n’ther toward his-opening (derivative A) or heterocyclization. Heterocyclizadon leads to a 1.9 mixture of the enantiopure poiysubstinued piperidhs B andpyrrolidines C.
We have carried out, starting from D-mannitol. the synthesis of new homochiral C2 symmetric bisaziridines which can be used as versatile building blocks in the synthesis of various biologically significant derivatives. We had previously reported of the synthesis’ and nucleophilic opening2 of suitably N-activated bisaziridines derived from 3,4-0-isopropylidene-D-mannitol. Nucleophiiic opening led after hetemcyclization tu polysubstitutedpipexidines B possessing four asymmetric centers, close in structureto glycosidase inhibitors. The cyclization followed in this case a 6-e&-ret
process, the C-2, C-3 diol involved in a cyclic acetal
preventingthe formation of a pyrrolidine ring thmugh a S-exe-ter-cyclization mode. Nu NHY PO /,
YHN
Op
NU A NuCH,
k
P- 1-methykthylidene P= CH2Ph
mwqy
+ N”C”~~HpNHY
HY
PO
B
1201
4 C
1202
The selective preparation
of functionalized
pyrrolidines
since, referring to Baldwin’s rules. the 5_exo-tet-cyclization tet process. We report here that bis-aziridines dihydroxy-2,Misubstituted
pyrr&dines.
basic structure of several biologically glycosidases.
Five membered
by the same strategy seemed a reasonable
mode is usually more favotuable
derived from 3,4-di-O-benzyl-D-mitol
Such skeletons are worthwhile active alkaloids
than the 6-endo-
are precursors of 3,4-
synthetic wets
such as dexine3
goal
or australin&,
sinee they have the inhibitors
acetamido azasugars have also recently been shown to be competitive
of many inhibitors
of /QV-acetylglucosaminase~.
australine
alexine
We anticipated
that the nucleophilic
enable the synthesis of pymAid.ine derivatives
ring opening substituted
this end we carried out the synthesis of bis-aziridine (Sa) or by a benzyloxycarbonyl 5 was synthesized
of conformationally
flexible
bis-aziridines
would
at C-2 and at C-5 by two different functions
and to
5 protected at the nitrogen either by a tert-butoxycarbonyl
group (Sb).
starting from 3,4-di-0-benzyl-D-mannitol
1 itself prepared
following
eu=Jj-
s
C, d
NY
BIIO
P
YN
DMF, 7VC, 5h. c) PhsP, PhC&,35oc a 1 Tscl, WrWne, 0°C. b) Wa d ) (C@@jfJ)&, EtsN, mF, 0°C to rt, 3h; or: CICC&HnPh, Et& C&&h,
2h, then WC, 0°C to a, 3h.
5h.
a known
1203
The tetrol 1 wss transformed into the ccmesponding diazidodio13 by sodium azide substitution of the corresponding primary ditosylate 2, itself pmparcd in 48% yield by conventional manner. Sodium azide substitution of 2 efkcted at 7OT during 5 hours resulted in 73% of3 besides 12% of the 1,~didcoxy-&tzidc+ D-mannopyranose 4.4 results from the competitive attack, allowed by the conformational flexibility of the carbon chain of the secondary hydroxyle group on the primary tosylate. When reacted with triphcnylphosphine.
as previously described for the 3.4-di-0-isopropylidene
derivativel, the diazidodio13 led to a mixture of the expected N-H bis-aziridine 5 and of the fumn 6. 30th derivatives were isolated in their N-protected form; the N-Boc bis-aziridine Sa and N-Cbz bis-aziridine 5b in respectively 53% and 47% yield, and the N-Boc-2,5-dlsminomethyl-3,4-dihydroxyfuran
6a in 17% yield. N-
Cbz-dihydroxytiuan 6b is farmed together with Sb,but has not been purifkd. The structure of the furanose 6a was established by its 1H and I3C NMR spectral data. It does not possess
the C2 symmetry
but the configuration
of D-glucose
and therefore occurs with inversion of
configuration at C-2 of D-mannitoL The formation of the furan 6 from the diazidodiol3 derived bis-iminophosphorane could result from a competitive
decomposition,
allowed
by the flexibility
of the carbon chain,
of the intermediate
oxazaphospholidine as depictul in the scheme.
We have car&d out the nuclcophilic ring opening of the N-Boc and N-Cbz activated bis-aziridines by azide and phenylthiola&! ions. When the reaction is effected in an aprotic medium, the nucleophilic opening of the first aziridk
ring is
followed by an intramolecular aminocyclization
leading to the formation of a piperidine or pyrrolidine
derivative. We found that in each case the formation
of the pynolidine ring largely prevailed.
Sodium azlde nucleophilic ring opening of Sa or Sb when effected in DMF in the presence of 10% of teaabutylammonium Sa the piperid&
iodide led to the pyrrolidines 7a and 7b in respectively 68% and 5 1% yield; starting fmm
&a was also isolated in 7% yield.
The reaction was oriented toward bis-opening by using guanidinium azide as nucleophile, the bisazirhline 5b led thus to the bis-amino derivative 9b very mildly in 92% yieid. In this reaction the guanidinium ionactedastheprotondonor. When reacted with sodium phenylthiolate, Sa led to a IO:1 mixture of the pyrmlidine 1Oa and of the piperidine lla,which where isolated in respectively 70% and 6% yield The aziridine Sb led to lob in 84% yield, and to traces of the corresponding pip&dine lib.
1204
7s 68%,
v YN
8a 7%; 8b ‘5%
_ 7b 51%
3
YHN N-3
K
s’;y& I
@b OBn &Ok3
BnO
PhSCH kn,
WNI,
.bOBn c)
H#JHY !
lOa a)
from&:
b) k-
w.
1.
lob
84%
IN(Bu)4 lo%, DMF, W’C,
H$l+=C(Nll&,
WC,
lle 20h; from5b:
896, llb Nak,
trace
IN(Bu)4 loo/o, DMF, 85~.
4h
20h. c) PhSh, HNa, DMF. 2O”C,3h.
flexible axafumnoses
homochiral
References
70%,
-kH.$Ph c!
bis-axiridines
versatile
of
D-ghtcose
and Notes
Dureault, A.; Greck,.C.; Deqezay, J.C. Tetrahedron Len., 1986,27, Le Merrer, Y.; Dureault, A.; GreckX.; Micas-Languin, D.; Gravier, Heterocycles, 1987,25, 541-548.
4157-4160.
C.; Depexay, J-C,
I.; Depexay, J.C. J. Org. Chem., 1989,54.
5324-5330.
2.
Dureault,
3.
Nash, R. J.; Feliows, L. E.; Dring, J. V.; Fleet.G. W. J.; Derome. A. E.; Hamor, T. A.; Scofield, A. M.; Watkin, D. J. Tetrahed?on L&t., 198% 29,2487-2490.
4.
Molyneux.
5.
Takaoka,
6.
Jurcxak, J., Bauer, T., Chmiebwski,
7.
All
A.; Tranchepain,
R. J.; Benson,
1198-1206
Y.; Kajimoto,
M.: Wong, R. Y.; Tropea. J.E.; Elbein. A.D. J. Nat. Prod. 1988.51. T.; Wong, C.-H. J. Org. C%em., 1993,58,4809-4812. M. Carbohydr. Res.. 1987,164,
new compounds were purified by silica-gel column chromatography spectmscopic means and elemental analyses.
(Received in France 17 November 1993; accepted 19 December 1993)
493-498. and were fully characterized
by
0040-4039(94)EOO15-P
2,SDisubstituted
Juliette
Pyrrolidines
from
Bis- Aziridines
Fitremann,
Annie Durhult
D-Mannitol-Derived
*, Jean-Claude
Depezay
Absburcl : Concise syntheses of 3,4-dihy&oxy-2,Sdisubstituted
pyrrolidines have been achieved starting from Dmannitol-detivedjkzibk L-Id0 bis-aziridkes. Nuckophilic ring opening of the N-Boc and the N-Cbz activated bisasiridines by phenylthiolate and azide ions has beenstudied ; the reaction can be oriented n’ther toward his-opening (derivative A) or heterocyclization. Heterocyclizadon leads to a 1.9 mixture of the enantiopure poiysubstinued piperidhs B andpyrrolidines C.
We have carried out, starting from D-mannitol. the synthesis of new homochiral C2 symmetric bisaziridines which can be used as versatile building blocks in the synthesis of various biologically significant derivatives. We had previously reported of the synthesis’ and nucleophilic opening2 of suitably N-activated bisaziridines derived from 3,4-0-isopropylidene-D-mannitol. Nucleophiiic opening led after hetemcyclization tu polysubstitutedpipexidines B possessing four asymmetric centers, close in structureto glycosidase inhibitors. The cyclization followed in this case a 6-e&-ret
process, the C-2, C-3 diol involved in a cyclic acetal
preventingthe formation of a pyrrolidine ring thmugh a S-exe-ter-cyclization mode. Nu NHY PO /,
YHN
Op
NU A NuCH,
k
P- 1-methykthylidene P= CH2Ph
mwqy
+ N”C”~~HpNHY
HY
PO
B
1201
4 C
1202
The selective preparation
of functionalized
pyrrolidines
since, referring to Baldwin’s rules. the 5_exo-tet-cyclization tet process. We report here that bis-aziridines dihydroxy-2,Misubstituted
pyrr&dines.
basic structure of several biologically glycosidases.
Five membered
by the same strategy seemed a reasonable
mode is usually more favotuable
derived from 3,4-di-O-benzyl-D-mitol
Such skeletons are worthwhile active alkaloids
than the 6-endo-
are precursors of 3,4-
synthetic wets
such as dexine3
goal
or australin&,
sinee they have the inhibitors
acetamido azasugars have also recently been shown to be competitive
of many inhibitors
of /QV-acetylglucosaminase~.
australine
alexine
We anticipated
that the nucleophilic
enable the synthesis of pymAid.ine derivatives
ring opening substituted
this end we carried out the synthesis of bis-aziridine (Sa) or by a benzyloxycarbonyl 5 was synthesized
of conformationally
flexible
bis-aziridines
would
at C-2 and at C-5 by two different functions
and to
5 protected at the nitrogen either by a tert-butoxycarbonyl
group (Sb).
starting from 3,4-di-0-benzyl-D-mannitol
1 itself prepared
following
eu=Jj-
s
C, d
NY
BIIO
P
YN
DMF, 7VC, 5h. c) PhsP, PhC&,35oc a 1 Tscl, WrWne, 0°C. b) Wa d ) (C@@jfJ)&, EtsN, mF, 0°C to rt, 3h; or: CICC&HnPh, Et& C&&h,
2h, then WC, 0°C to a, 3h.
5h.
a known
1203
The tetrol 1 wss transformed into the ccmesponding diazidodio13 by sodium azide substitution of the corresponding primary ditosylate 2, itself pmparcd in 48% yield by conventional manner. Sodium azide substitution of 2 efkcted at 7OT during 5 hours resulted in 73% of3 besides 12% of the 1,~didcoxy-&tzidc+ D-mannopyranose 4.4 results from the competitive attack, allowed by the conformational flexibility of the carbon chain of the secondary hydroxyle group on the primary tosylate. When reacted with triphcnylphosphine.
as previously described for the 3.4-di-0-isopropylidene
derivativel, the diazidodio13 led to a mixture of the expected N-H bis-aziridine 5 and of the fumn 6. 30th derivatives were isolated in their N-protected form; the N-Boc bis-aziridine Sa and N-Cbz bis-aziridine 5b in respectively 53% and 47% yield, and the N-Boc-2,5-dlsminomethyl-3,4-dihydroxyfuran
6a in 17% yield. N-
Cbz-dihydroxytiuan 6b is farmed together with Sb,but has not been purifkd. The structure of the furanose 6a was established by its 1H and I3C NMR spectral data. It does not possess
the C2 symmetry
but the configuration
of D-glucose
and therefore occurs with inversion of
configuration at C-2 of D-mannitoL The formation of the furan 6 from the diazidodiol3 derived bis-iminophosphorane could result from a competitive
decomposition,
allowed
by the flexibility
of the carbon chain,
of the intermediate
oxazaphospholidine as depictul in the scheme.
We have car&d out the nuclcophilic ring opening of the N-Boc and N-Cbz activated bis-aziridines by azide and phenylthiola&! ions. When the reaction is effected in an aprotic medium, the nucleophilic opening of the first aziridk
ring is
followed by an intramolecular aminocyclization
leading to the formation of a piperidine or pyrrolidine
derivative. We found that in each case the formation
of the pynolidine ring largely prevailed.
Sodium azlde nucleophilic ring opening of Sa or Sb when effected in DMF in the presence of 10% of teaabutylammonium Sa the piperid&
iodide led to the pyrrolidines 7a and 7b in respectively 68% and 5 1% yield; starting fmm
&a was also isolated in 7% yield.
The reaction was oriented toward bis-opening by using guanidinium azide as nucleophile, the bisazirhline 5b led thus to the bis-amino derivative 9b very mildly in 92% yieid. In this reaction the guanidinium ionactedastheprotondonor. When reacted with sodium phenylthiolate, Sa led to a IO:1 mixture of the pyrmlidine 1Oa and of the piperidine lla,which where isolated in respectively 70% and 6% yield The aziridine Sb led to lob in 84% yield, and to traces of the corresponding pip&dine lib.
1204
7s 68%,
v YN
8a 7%; 8b ‘5%
_ 7b 51%
3
YHN N-3
K
s’;y& I
@b OBn &Ok3
BnO
PhSCH kn,
WNI,
.bOBn c)
H#JHY !
lOa a)
from&:
b) k-
w.
1.
lob
84%
IN(Bu)4 lo%, DMF, W’C,
H$l+=C(Nll&,
WC,
lle 20h; from5b:
896, llb Nak,
trace
IN(Bu)4 loo/o, DMF, 85~.
4h
20h. c) PhSh, HNa, DMF. 2O”C,3h.
flexible axafumnoses
homochiral
References
70%,
-kH.$Ph c!
bis-axiridines
versatile
of
D-ghtcose
and Notes
Dureault, A.; Greck,.C.; Deqezay, J.C. Tetrahedron Len., 1986,27, Le Merrer, Y.; Dureault, A.; GreckX.; Micas-Languin, D.; Gravier, Heterocycles, 1987,25, 541-548.
4157-4160.
C.; Depexay, J-C,
I.; Depexay, J.C. J. Org. Chem., 1989,54.
5324-5330.
2.
Dureault,
3.
Nash, R. J.; Feliows, L. E.; Dring, J. V.; Fleet.G. W. J.; Derome. A. E.; Hamor, T. A.; Scofield, A. M.; Watkin, D. J. Tetrahed?on L&t., 198% 29,2487-2490.
4.
Molyneux.
5.
Takaoka,
6.
Jurcxak, J., Bauer, T., Chmiebwski,
7.
All
A.; Tranchepain,
R. J.; Benson,
1198-1206
Y.; Kajimoto,
M.: Wong, R. Y.; Tropea. J.E.; Elbein. A.D. J. Nat. Prod. 1988.51. T.; Wong, C.-H. J. Org. C%em., 1993,58,4809-4812. M. Carbohydr. Res.. 1987,164,
new compounds were purified by silica-gel column chromatography spectmscopic means and elemental analyses.
(Received in France 17 November 1993; accepted 19 December 1993)
493-498. and were fully characterized
by