- Email: [email protected]
Synthesis of a 2-hydroxymethyl-dihydropyridone-system as a flexible building block for the preparation of azasugars
~)
Tetrahedron Letters, Vol. 36, No. 28, pp. 4983-4984, 1995 Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
Pergamon 0040-4039(95)00957-4
Synthesis of a 2-Hydroxymethyi-dihydropyridone~System as a Flexible Building Block for the Preparation of Azasugars H a n s - J o s e f Aitenbach I and R a l f W i s c h n a t
FB 9 - BergischeUniversitat- GH - Wuppertal,D - 42119 Wuppcrtal,Germany
Abstract: mCPBAinducedoxidativecyclizationof the aminoalcoholla under completestereocontrol,gene-
rating after acetalformationa new diastereomericallypure key intermediate2b for the flexiblesynthesisof azasugars. 2b couldbe convertedto protectedrac-mannonojirimycin3 in onlythree steps. Polyhydroxylated piperidines H, related to the naturally occurring gluco configurated nojirimycin, can be regarded as azasugars and have attracted a lot of interest in recent years due to the observation that they often have a wide range of biological activities.1 Therefore much effort has already been undertaken to develop efficient synthetic routes to divergent azasugars or their derivatives respectively, but most of these approaches only lead to specific substituted systems and are not generally applicable.1 Our aim was to synthesize central building blocks like I or H I which can be functionalized to various azasugar systems H in a very flexible manner. Recently we have published the synthesis of a 5,6-dihydro-2(1H)-pyridone building block I. 2
,,,OR 0R ~ R < ~ : :
HO HO
I
0
H ~ lI
R"O.... Eli
allo, altro, rnanno, gluco, galacto, ido
Scheme 1.
In this report we wish to describe a concise route to a related key intermediate 2b which should be useful for the synthesis of quite a lot of azasugars, as a corresponding dihydropyrane system (X---O and K---CH2OH) has been transformed to different pyranoses.3,4 Besides starting from sugars5 the dihydropyrone system has been synthesized from a furylalcohol precursor (X=O and K=CH2OH) by an oxidative rearrangement. 5 It has been shown by Zhou 6 that such a transformation can also be accomplished with furylamides (X=NTs and R=alkyl). But there was no report on the use of a system with XfNTs and R=CH2OH.
~
R
a,b ~
XH 1
2a R'=H R=CH2OAcXfNTs 2bR'=Et R=CH2OAe X=NTs
> 95%de R'O""
R
la R=CI~OAc XffiNTs
2
Scheme 2, Reagentl m,d conditions: a. mCPBA,CH2C12,30 *C, 4.5 h (70%),b. EtOH, Ce(NH4)2(NO3)6,RT (95%)
Starting from the readily available furylglycine7 the protected aminoalcohol l a could be synthesized over three steps in 50% overall yield. Its oxidative eyclization with mCPBA using a modified procedure of a method 4983
4984
described by Zhou et al.6 gave the diastereomerically pure dihydropyridone 2a aRer recrystallization as a white solid in excellent yield. The hemiacetal 2a could be converted to the more stable acetal 2b 8 by treating a solution of 2a in EtOH with a catalytic amount of CeIV-salts9 at room temperature, under these conditions the other epimer was not observed. However, upon chromatography on silieagel with EtOAc,/n-hexane 2a and 2b underwent epimerization with predominant formation of the other anomer, manifested by IH NMR. This observation allows the conclusion that the isomer isolated directly after the reaction is formed under kinetic control leading to the trans-cordigurated system 2a. In order to probe its potential the new key compound 2b was converted in only three steps to protected marmonojirimycin 3. Starting from 2b Luche reduction 10 followed by protection of the resulting alcohol and consecutive cis-dihydroxylation employing the recent method of Shing et al.ll leads exclusively to the protected mannonojirimycin-derivative 3, at least 95% diastereomerically pure as revealed by 1H NMR, in 68% yield. As furylglycine is well known in both enantiomeric forms 12 the described methodology should also provide azasugars in their enantiomerieal pure form. Work is in progress to generate both enantiomers of the building block 2b and to develop routes to homochiral azasugars in various ways.
Ts•
HO
Ac
C, d, e]~
2b
3
Scheme 3. Reagents and conditions: c. NaBH4, CeC13,0 °C,1 h, (95%), d. DMAP, Ac20, CH2C12,NEt3, (93%), e. RuCI3,NaIO4, CH3CN,EtOAC, H20 (3:3:1), 30 sec, (68%) References and Notes
For an excellent reviewon the synthesisand biologicalactivityof deoxynojirimycinand analogues, see: Hughes, A. B. ; Rudge, A. J. Natural Product Reports 1994, pp. 135 - 162. SystemI was prepared by a chiral pool approach starting from serine: Altenbach,H.-L; Himmeldirk,K. B. TetrahedronAsymmetry 1995, in press. (a) Achnmtowicz,O. in Organic b~vnthesisToday and Tomorrow, Trost, B. M.; Hudchinson,C. P,. Eds.; Pergamon
9. 10. 11. 12.
Press: Oxford. 1981, pp. 307 - 318. (b) Achmatowicz,O.; Bielski, R. Carbohydr. Res. 1977, 55, 165. Lichtenthaler, F. W. Building Blocks from Sugars. InModern S),ntheticMethods Ed. R. Scheffold, VCH: Weinheim, 1992and referencescited therein. For a comprehensivereviewon hexenulosessee: Holder, L. N. Chem. Rev. 1982, 82, 287. Zhou, W. S.; Xie, W. G.; Lu, Z. H.; Pan, X. F. Tetrahedron Left. 1995, 36, 1291. Onabe, K. J. Antibiot. (Japan) 1978, 31,555. Spectral data of2b. 1HNMR (CDC13,400 MHz);5 --- 1.27(t, 3H, OCH2CH3),2.07(s, 3H, OAt), 2.41(s, 3H, Ph-C~__Ha), 3.72(m, 1H, OCrI2), 4.01(m, lr~ OCHa), 4.26(m,1B, crtca20ac), 5.6s(a, 1H, 3j=4.5Hz, CH-CH=Ch'),5.86(d, IH, 31=10.5Hz, CH-CH=-CI-D,6.84(dd, 1H, 3I=10.5Hz, 3j=4.5Hz, CH-CH=CIO,13CNMR (CDCI3, 100 Mhz); 5 = 14.88, (OCH2,{~) , 20.91(OAc), 21.60(Ph-4~H3),60.05(_QHCH2OAc),64.51(O~H2CH3), 64.83(CHCH2OAc),79.5(.~HOCH2 CH3), 127.18, 130.14, 136.1, 143.46 ~__h-CH3), 144.3(CH-_CH=CH),127.37(CH-CH=(~-I),I91.81(C=O) white solidi m.p.111-113 *C. Iranpoor, N.; MothaghinedhacLE. Tetrahedron 1994, .s0, 1859. Luche, J. L.; Rodriguez-Hahn,L.; Crabbe,P. ~ Chem. Soc., Chem. Commun. 1978, 601. Shing, T. K. M.; Tai, V. W. F.; Tam, E. K. W.Angew. Chem. Int. Ed. Engl. 1994, 33, 2312. Williams,1L M. Synthesis ofOpticalActive c¢-AminoAcidy, PergamonPress: Oxford. 1989, pp. 48, 226, 268
(Received in Germany 31 March 1995; accepted 22 May 1995)
Tetrahedron Letters, Vol. 36, No. 28, pp. 4983-4984, 1995 Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
Pergamon 0040-4039(95)00957-4
Synthesis of a 2-Hydroxymethyi-dihydropyridone~System as a Flexible Building Block for the Preparation of Azasugars H a n s - J o s e f Aitenbach I and R a l f W i s c h n a t
FB 9 - BergischeUniversitat- GH - Wuppertal,D - 42119 Wuppcrtal,Germany
Abstract: mCPBAinducedoxidativecyclizationof the aminoalcoholla under completestereocontrol,gene-
rating after acetalformationa new diastereomericallypure key intermediate2b for the flexiblesynthesisof azasugars. 2b couldbe convertedto protectedrac-mannonojirimycin3 in onlythree steps. Polyhydroxylated piperidines H, related to the naturally occurring gluco configurated nojirimycin, can be regarded as azasugars and have attracted a lot of interest in recent years due to the observation that they often have a wide range of biological activities.1 Therefore much effort has already been undertaken to develop efficient synthetic routes to divergent azasugars or their derivatives respectively, but most of these approaches only lead to specific substituted systems and are not generally applicable.1 Our aim was to synthesize central building blocks like I or H I which can be functionalized to various azasugar systems H in a very flexible manner. Recently we have published the synthesis of a 5,6-dihydro-2(1H)-pyridone building block I. 2
,,,OR 0R ~ R < ~ : :
HO HO
I
0
H ~ lI
R"O.... Eli
allo, altro, rnanno, gluco, galacto, ido
Scheme 1.
In this report we wish to describe a concise route to a related key intermediate 2b which should be useful for the synthesis of quite a lot of azasugars, as a corresponding dihydropyrane system (X---O and K---CH2OH) has been transformed to different pyranoses.3,4 Besides starting from sugars5 the dihydropyrone system has been synthesized from a furylalcohol precursor (X=O and K=CH2OH) by an oxidative rearrangement. 5 It has been shown by Zhou 6 that such a transformation can also be accomplished with furylamides (X=NTs and R=alkyl). But there was no report on the use of a system with XfNTs and R=CH2OH.
~
R
a,b ~
XH 1
2a R'=H R=CH2OAcXfNTs 2bR'=Et R=CH2OAe X=NTs
> 95%de R'O""
R
la R=CI~OAc XffiNTs
2
Scheme 2, Reagentl m,d conditions: a. mCPBA,CH2C12,30 *C, 4.5 h (70%),b. EtOH, Ce(NH4)2(NO3)6,RT (95%)
Starting from the readily available furylglycine7 the protected aminoalcohol l a could be synthesized over three steps in 50% overall yield. Its oxidative eyclization with mCPBA using a modified procedure of a method 4983
4984
described by Zhou et al.6 gave the diastereomerically pure dihydropyridone 2a aRer recrystallization as a white solid in excellent yield. The hemiacetal 2a could be converted to the more stable acetal 2b 8 by treating a solution of 2a in EtOH with a catalytic amount of CeIV-salts9 at room temperature, under these conditions the other epimer was not observed. However, upon chromatography on silieagel with EtOAc,/n-hexane 2a and 2b underwent epimerization with predominant formation of the other anomer, manifested by IH NMR. This observation allows the conclusion that the isomer isolated directly after the reaction is formed under kinetic control leading to the trans-cordigurated system 2a. In order to probe its potential the new key compound 2b was converted in only three steps to protected marmonojirimycin 3. Starting from 2b Luche reduction 10 followed by protection of the resulting alcohol and consecutive cis-dihydroxylation employing the recent method of Shing et al.ll leads exclusively to the protected mannonojirimycin-derivative 3, at least 95% diastereomerically pure as revealed by 1H NMR, in 68% yield. As furylglycine is well known in both enantiomeric forms 12 the described methodology should also provide azasugars in their enantiomerieal pure form. Work is in progress to generate both enantiomers of the building block 2b and to develop routes to homochiral azasugars in various ways.
Ts•
HO
Ac
C, d, e]~
2b
3
Scheme 3. Reagents and conditions: c. NaBH4, CeC13,0 °C,1 h, (95%), d. DMAP, Ac20, CH2C12,NEt3, (93%), e. RuCI3,NaIO4, CH3CN,EtOAC, H20 (3:3:1), 30 sec, (68%) References and Notes
For an excellent reviewon the synthesisand biologicalactivityof deoxynojirimycinand analogues, see: Hughes, A. B. ; Rudge, A. J. Natural Product Reports 1994, pp. 135 - 162. SystemI was prepared by a chiral pool approach starting from serine: Altenbach,H.-L; Himmeldirk,K. B. TetrahedronAsymmetry 1995, in press. (a) Achnmtowicz,O. in Organic b~vnthesisToday and Tomorrow, Trost, B. M.; Hudchinson,C. P,. Eds.; Pergamon
9. 10. 11. 12.
Press: Oxford. 1981, pp. 307 - 318. (b) Achmatowicz,O.; Bielski, R. Carbohydr. Res. 1977, 55, 165. Lichtenthaler, F. W. Building Blocks from Sugars. InModern S),ntheticMethods Ed. R. Scheffold, VCH: Weinheim, 1992and referencescited therein. For a comprehensivereviewon hexenulosessee: Holder, L. N. Chem. Rev. 1982, 82, 287. Zhou, W. S.; Xie, W. G.; Lu, Z. H.; Pan, X. F. Tetrahedron Left. 1995, 36, 1291. Onabe, K. J. Antibiot. (Japan) 1978, 31,555. Spectral data of2b. 1HNMR (CDC13,400 MHz);5 --- 1.27(t, 3H, OCH2CH3),2.07(s, 3H, OAt), 2.41(s, 3H, Ph-C~__Ha), 3.72(m, 1H, OCrI2), 4.01(m, lr~ OCHa), 4.26(m,1B, crtca20ac), 5.6s(a, 1H, 3j=4.5Hz, CH-CH=Ch'),5.86(d, IH, 31=10.5Hz, CH-CH=-CI-D,6.84(dd, 1H, 3I=10.5Hz, 3j=4.5Hz, CH-CH=CIO,13CNMR (CDCI3, 100 Mhz); 5 = 14.88, (OCH2,{~) , 20.91(OAc), 21.60(Ph-4~H3),60.05(_QHCH2OAc),64.51(O~H2CH3), 64.83(CHCH2OAc),79.5(.~HOCH2 CH3), 127.18, 130.14, 136.1, 143.46 ~__h-CH3), 144.3(CH-_CH=CH),127.37(CH-CH=(~-I),I91.81(C=O) white solidi m.p.111-113 *C. Iranpoor, N.; MothaghinedhacLE. Tetrahedron 1994, .s0, 1859. Luche, J. L.; Rodriguez-Hahn,L.; Crabbe,P. ~ Chem. Soc., Chem. Commun. 1978, 601. Shing, T. K. M.; Tai, V. W. F.; Tam, E. K. W.Angew. Chem. Int. Ed. Engl. 1994, 33, 2312. Williams,1L M. Synthesis ofOpticalActive c¢-AminoAcidy, PergamonPress: Oxford. 1989, pp. 48, 226, 268
(Received in Germany 31 March 1995; accepted 22 May 1995)