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Reactions and determination of stereochemistry of 3-methylenecepham derivatives
Tetrahedron LettersNo. 31, pp 3241 - 3244 1972. PergsmonPrese. Printedin GreatBritsia.
REACTIONS AND DETERMINATION OF STEREOCHEMISTRY OF 3-METHYLENECEPHAM DERIVATIVES Michlhlko Ochlal, Osaml Akl, Aklra Morimoto, and Tallti Okada Central Research Division, Takeda Chemical Industries, Ltd., Juso, Osaka, Japan (Reoelved in Japu 23 June 19721reoeivedin UK
for
Publloatism 26 J~lsn 1972)
1,2) In the previous communications, we reported the facile syntheses of a novel class of cephalosporlns, 3-methylenecepham derivatives, by an electrochemical reduction or chromium(I1) salts reduction of cephalosporanic acids. This communication describes some aspects of chemical reactions of these compounds and also the establishment of the stereochemistry at position 4. Esterlficatlon of Ia by the conventional treatment with diazomethane gave the 3-methylenecepimn methyl ester (Ib), m.p. 145-147'C, IR (KBr)l 1765 cm-l (R-lactam), NMR (a, 100 MC, CDC13): 3.17 and 3.68 (two doublets, 2H, 2-C&), 5.10 (singlet, lH, 4-CH), 5.21 (broad doublet, 2H, C=ClX2),5.39 6-cg), 5.69 (doublet of doublet, lH, 7-CH). perbenzoic
acid
(doublet, lH,
Oxidation of Ib with g-chloro-
in dichloromethane provided a S-sulfoxide* (II), m-P. 18%
190°C, IR (KBr)r 1770 cm-'(S-lactam), NMR (a, 100 MC, CDC13): 3.67 (doublet, 2H, 2-(X2), 5.19 (Singlet,
18,
4-CH), 5.40 and 5.69 (two singlets, 2H, C=Cg2)s
5.97 (doublet of doublet, lH, 7-(X). The treatment of II with pyridine192)afforded 3-methyl-3-oephem S-sulfoxlde (IVa), m.p. 213-215'C, IR (KBr): 1760 om-1 (B-laotam), NMR (a, 100 MC, d6DASO): 2.03 (singlet, 3H, 3-CX3), 3.71 (singlet, 2H, 2-Cz2), 4.91 (doublet, lH, 6-cg), 5.93 (doublet of doublet, lH, 7-Cg)*
The characterization of IVa
All the new compounds gave satisfactory combustion analyses. *
a-Sulfoxide corresponds to (R)-configuration and S-sulfoxlde to (S)-configuratlon.3)
3241
no. 31
3242
was established by the direct comparison with a speolmen obtained from the known compound (IVb)3) by hydrolysis with zinc In acetic acid4) follored by esterificatlon with diazomethane. The treatment of Ib with an equlmolar amount of N,N-dichlorourethane in THF gave another sulfoxlde compound (III), m.p. 158-159°c, IR (KBr)r 1775 cm-l (6-lactam), NMR (8, 100 MC, CDC13): 3.60 and 4.00 (two doublets, 2H, 2+X2), 4.76 (doublet, lH, 6-(X$, 5.04 (singlet, lH, 4-C@, lH, 7-(X), 5.46 (doublet, 2H, C=CE2).
5.46 (doublet of doublet,
III was isomerlzed In pyrldine to the
3-methyl-3-cephem sulfoxlde (Va), m.p. 161-163*c, IR (KB~): 1790 cm-1 (Slactam), NMR (6, 100 MC, CDC13)r 2.21 (singlet, 3H, 3-clJ3),3.40 and 4.00 (two doublets, 2H, 2-Cg2), 4.57 (doublet, lH, 6-CZJ),5.49 (doublet of doublet, lH, 7-W).
Both IVa and Va gave the same sulfone derivative (VI) upon
further oxidation with m-chloroperbenzoic acid.
The results clearly Indicate
that III and Va should be assigned a-aonfiguration at position 1.
Conversion
of the known compound (Vb)3) to Va confirmed this configuration, This assignment was further corroborated by the hydrogen bonding studies In NMR.
As 1s shown in the Table a change in solvent (CDC13+d6-DMSC)
Induces a down field shift of 1.71 ppm in the resonance of N?lin III indicative of an Intermolecular hydrogen bonding to DMSO.
The S-sulfoxide (II), This Is in good accord with
however, exhibits only a negligible shift.
the phenomena observed with other cephalosporin sulfoxide compounds,5) The present stereospeclfic oxidation of II with N,N -dichlorourethane is of interest beoause no other method has been known for the stereospeciflc synthesis of a-sulfoxides of cephalosporlns.6)
It is likely that chlorln-
ation of Ib might form the (S)-sulfonlum chloride (VIT) which upon subsequent hydrolysis wlth inversion would give the (R)-sulfoxlde (III), Taking Into consideration that the S -0
bond has a similar anisotropic
effect7)as an ’acetylene bond, the anisotropic effect of a-andS -sulfoxldes (III, II) on each proton at position 4 was examined.
The proton at
position 4 is shielded by 0.06 ppm In the a-sulfoxlde (11-I)and deshlelded by 0.09 ppm In the6 -sulfoxlde (II) compared with the sulfide (Ib). two conformational possibilities, A and B, for both II and III.
There are The proton
3243
Eo. 31
Table
Hydrogen Bonding Studies VA
Compound
Solvent Induced Shift
Chemical Shift for NH_ (appm)
Solvent
8.09 8.21 1
II III
A=-0.12 A=-1.71
L CR3 COOR"
(IV)
CH COOR3 (V)
(III)
Va:R"=CHj b:R"=CH CC1 2 3
RCONR RCO
Ii
cooca3
(VII)
X= 0 or
Y=lone
lone pair electrons pair electrons or 0
3244
No. 31
at position 4 can take four possible situations (Ha, Hb, Hc, Hd). Examlnatlon of a Dreldlng model indicated that only the B-configuration (Ha) for the proton at posltlon 4 In the conformation A satisfies the above anlsotropy shift values.8) The same stereochemistry was achieved with a 3-methylenecepham derlvatlve by means of lanthanlde-induced shifts combined with computer calculation, which will be published elsewhere.9)
Acknowledgement
The authors are grateful to Dr. K. Morlta for his
encouragement throughout this work.
References 1.
M. Ochiai, 0. Aki, A. Morimoto, T. Okada, K. Shinozaki, and Y. Asa&
2.
Tetrahedron Letters, in press. M. Ochiai, 0. Aki, A. Morimoto, T. Okada, and H. Shimadzu, J. C. S. Chem.
3. 4. 5. 6.
7.
a. 9.
&g&g., in press. G. V. Kaiser, R. D. G. Cooper, R. E. Koehler, C. F. Murphy, J. A. Webber, I. G. Wright, and E. M. Van Heyningen, J. Oru. Chem., & 2430 (1970). R. B. Woodward, K. Heualer, J. Goateli, P. Naegeli, W. Oppolzer, R. Ramage, S. Ranganathan, and H. VorbrUgger, J. Am. Chem. Sot., $& 852 (1966). R. D. 0. Cooper, P. V. Demarco, C. F. Murphy, and L. A. Spangle, J. Chem. sot. (C), 340 (1970). Brief comment of the oxidation of cephaloaporina and penicillins is given; D. H. R. Barton, F. Comer, D. G. T. Greig, P. G. Ssmmea, C. M. Cooper, G. Hewitt, and W. G. E. Underwood, J. Chem. SOC. (Cl, 3540 (1971). K. W. Buck, A. B. Foster, W. D. Pardoe, M. H. @dir, and J. M. Webber, Chem. Comm., 739 (1966); A. B. Foater, T. D. Inch, M. H. &dir, and J. M. Webber, j&&., 1086 (1968). For ar&.ogous discuasiona, see the reference 5. M. O&i&, E. Mizuta, 0. Aki, A. Morimoto, and T. Okada, Tetrahedron Letters, in press.
REACTIONS AND DETERMINATION OF STEREOCHEMISTRY OF 3-METHYLENECEPHAM DERIVATIVES Michlhlko Ochlal, Osaml Akl, Aklra Morimoto, and Tallti Okada Central Research Division, Takeda Chemical Industries, Ltd., Juso, Osaka, Japan (Reoelved in Japu 23 June 19721reoeivedin UK
for
Publloatism 26 J~lsn 1972)
1,2) In the previous communications, we reported the facile syntheses of a novel class of cephalosporlns, 3-methylenecepham derivatives, by an electrochemical reduction or chromium(I1) salts reduction of cephalosporanic acids. This communication describes some aspects of chemical reactions of these compounds and also the establishment of the stereochemistry at position 4. Esterlficatlon of Ia by the conventional treatment with diazomethane gave the 3-methylenecepimn methyl ester (Ib), m.p. 145-147'C, IR (KBr)l 1765 cm-l (R-lactam), NMR (a, 100 MC, CDC13): 3.17 and 3.68 (two doublets, 2H, 2-C&), 5.10 (singlet, lH, 4-CH), 5.21 (broad doublet, 2H, C=ClX2),5.39 6-cg), 5.69 (doublet of doublet, lH, 7-CH). perbenzoic
acid
(doublet, lH,
Oxidation of Ib with g-chloro-
in dichloromethane provided a S-sulfoxide* (II), m-P. 18%
190°C, IR (KBr)r 1770 cm-'(S-lactam), NMR (a, 100 MC, CDC13): 3.67 (doublet, 2H, 2-(X2), 5.19 (Singlet,
18,
4-CH), 5.40 and 5.69 (two singlets, 2H, C=Cg2)s
5.97 (doublet of doublet, lH, 7-(X). The treatment of II with pyridine192)afforded 3-methyl-3-oephem S-sulfoxlde (IVa), m.p. 213-215'C, IR (KBr): 1760 om-1 (B-laotam), NMR (a, 100 MC, d6DASO): 2.03 (singlet, 3H, 3-CX3), 3.71 (singlet, 2H, 2-Cz2), 4.91 (doublet, lH, 6-cg), 5.93 (doublet of doublet, lH, 7-Cg)*
The characterization of IVa
All the new compounds gave satisfactory combustion analyses. *
a-Sulfoxide corresponds to (R)-configuration and S-sulfoxlde to (S)-configuratlon.3)
3241
no. 31
3242
was established by the direct comparison with a speolmen obtained from the known compound (IVb)3) by hydrolysis with zinc In acetic acid4) follored by esterificatlon with diazomethane. The treatment of Ib with an equlmolar amount of N,N-dichlorourethane in THF gave another sulfoxlde compound (III), m.p. 158-159°c, IR (KBr)r 1775 cm-l (6-lactam), NMR (8, 100 MC, CDC13): 3.60 and 4.00 (two doublets, 2H, 2+X2), 4.76 (doublet, lH, 6-(X$, 5.04 (singlet, lH, 4-C@, lH, 7-(X), 5.46 (doublet, 2H, C=CE2).
5.46 (doublet of doublet,
III was isomerlzed In pyrldine to the
3-methyl-3-cephem sulfoxlde (Va), m.p. 161-163*c, IR (KB~): 1790 cm-1 (Slactam), NMR (6, 100 MC, CDC13)r 2.21 (singlet, 3H, 3-clJ3),3.40 and 4.00 (two doublets, 2H, 2-Cg2), 4.57 (doublet, lH, 6-CZJ),5.49 (doublet of doublet, lH, 7-W).
Both IVa and Va gave the same sulfone derivative (VI) upon
further oxidation with m-chloroperbenzoic acid.
The results clearly Indicate
that III and Va should be assigned a-aonfiguration at position 1.
Conversion
of the known compound (Vb)3) to Va confirmed this configuration, This assignment was further corroborated by the hydrogen bonding studies In NMR.
As 1s shown in the Table a change in solvent (CDC13+d6-DMSC)
Induces a down field shift of 1.71 ppm in the resonance of N?lin III indicative of an Intermolecular hydrogen bonding to DMSO.
The S-sulfoxide (II), This Is in good accord with
however, exhibits only a negligible shift.
the phenomena observed with other cephalosporin sulfoxide compounds,5) The present stereospeclfic oxidation of II with N,N -dichlorourethane is of interest beoause no other method has been known for the stereospeciflc synthesis of a-sulfoxides of cephalosporlns.6)
It is likely that chlorln-
ation of Ib might form the (S)-sulfonlum chloride (VIT) which upon subsequent hydrolysis wlth inversion would give the (R)-sulfoxlde (III), Taking Into consideration that the S -0
bond has a similar anisotropic
effect7)as an ’acetylene bond, the anisotropic effect of a-andS -sulfoxldes (III, II) on each proton at position 4 was examined.
The proton at
position 4 is shielded by 0.06 ppm In the a-sulfoxlde (11-I)and deshlelded by 0.09 ppm In the6 -sulfoxlde (II) compared with the sulfide (Ib). two conformational possibilities, A and B, for both II and III.
There are The proton
3243
Eo. 31
Table
Hydrogen Bonding Studies VA
Compound
Solvent Induced Shift
Chemical Shift for NH_ (appm)
Solvent
8.09 8.21 1
II III
A=-0.12 A=-1.71
L CR3 COOR"
(IV)
CH COOR3 (V)
(III)
Va:R"=CHj b:R"=CH CC1 2 3
RCONR RCO
Ii
cooca3
(VII)
X= 0 or
Y=lone
lone pair electrons pair electrons or 0
3244
No. 31
at position 4 can take four possible situations (Ha, Hb, Hc, Hd). Examlnatlon of a Dreldlng model indicated that only the B-configuration (Ha) for the proton at posltlon 4 In the conformation A satisfies the above anlsotropy shift values.8) The same stereochemistry was achieved with a 3-methylenecepham derlvatlve by means of lanthanlde-induced shifts combined with computer calculation, which will be published elsewhere.9)
Acknowledgement
The authors are grateful to Dr. K. Morlta for his
encouragement throughout this work.
References 1.
M. Ochiai, 0. Aki, A. Morimoto, T. Okada, K. Shinozaki, and Y. Asa&
2.
Tetrahedron Letters, in press. M. Ochiai, 0. Aki, A. Morimoto, T. Okada, and H. Shimadzu, J. C. S. Chem.
3. 4. 5. 6.
7.
a. 9.
&g&g., in press. G. V. Kaiser, R. D. G. Cooper, R. E. Koehler, C. F. Murphy, J. A. Webber, I. G. Wright, and E. M. Van Heyningen, J. Oru. Chem., & 2430 (1970). R. B. Woodward, K. Heualer, J. Goateli, P. Naegeli, W. Oppolzer, R. Ramage, S. Ranganathan, and H. VorbrUgger, J. Am. Chem. Sot., $& 852 (1966). R. D. 0. Cooper, P. V. Demarco, C. F. Murphy, and L. A. Spangle, J. Chem. sot. (C), 340 (1970). Brief comment of the oxidation of cephaloaporina and penicillins is given; D. H. R. Barton, F. Comer, D. G. T. Greig, P. G. Ssmmea, C. M. Cooper, G. Hewitt, and W. G. E. Underwood, J. Chem. SOC. (Cl, 3540 (1971). K. W. Buck, A. B. Foster, W. D. Pardoe, M. H. @dir, and J. M. Webber, Chem. Comm., 739 (1966); A. B. Foater, T. D. Inch, M. H. &dir, and J. M. Webber, j&&., 1086 (1968). For ar&.ogous discuasiona, see the reference 5. M. O&i&, E. Mizuta, 0. Aki, A. Morimoto, and T. Okada, Tetrahedron Letters, in press.