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Cis- and trans-fused Di-tetrahydropyrans by rearrangement of steroidal spiroacetals
Tetrahedron Letters, Vol. 36, No. 40, pp. 7309-7312, 1995
Pergamon
Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(95)01472-1
Cis- and Trans-Fused Di-Tetrahydropyrans by Rearrangement
of Steroidal Spiroacetals Rosa L. Dorta, Raimundo Freire, Angeles Martfn, Ernesto Su~ez* Institutode Productos Naturales y Agrobiologfadel C.S.I.C., Carretera de La Esperanza3, 38206-LaLaguna, Tenerife,Spain Thierry Prang6 L.U.R.E., Universit6Paris-Sud,Paris, 91405 ORSAY, Cedex, France
Abstract: A new method for the synthesis of steroidal cis- and trans-fused di-tetrahydropyrans (1,6-dioxadecalins ) by reduction with DIBAH of derivatives of 1,6-dioxaspiro[4.5 ]decan-l O-yl methanesulfonate is described.
Many secondary metabolites from a large variety of natural sources exhibit a 1,6-dioxadecalin rings system in their structures. 1 In more of the cases the rings of this system are trans-fused (brevetoxins, ciguatoxins, gambieric acids, etc.) but some examples of cis-fused rings can be found in maitotoxin2 (rings L/M and N/O) and the halichondrins.3 The important biological activity of such compounds and the chemical complexity of their structures have generated a great interest amongst chemists and biologists.4
H
Scheme 1 H
We have recently described the preparation of chiral spiroacetals using an intramolecular hydrogen abstraction reaction promoted by alkoxy radicals. 5 Spiroacetals are also substructures of many secondary metabolites with interesting biological activities and hence the goal of considerable synthetic work. 6 During this study we envisaged that rearrangement of 0t-hydroxy-spiroacetals to a 1,6-dioxadecalin system can take place as shown in Scheme 1, if we were able to achieve the reduction of the spiroacetal7 with good chemoand stereoselectivity and also transform the hydroxyl into a good leaving group. In theory all possible isomers of the 1,6-dioxadecalin system can be obtained by using this methodology provided we can change the stereochemistry of the reduction and that of the leaving group. As models we have prepared steroidal methanesulfonates 2 and 6 from alcohols 1 and 5 respectively (Scheme 2), resulting from the reduction with NaBH 4 of the corresponding ketone which in turn can be obtained by Lewis acid-mediated rearrangement of 23-oxo-diosgenin.8 7309
13113
OR
o.o-
1R=H 2R=Ms
3
4
7
8
OR
5R=H 6R=Ms
Scheme 2
Figure 1. X-Ray of compound 3
Figure 2. X-Ray of compound 4
The methanesulfonate 2 was reduced with DIBAH (7 equiv) in CH2CI2 at room temperature for 2.5 h to give, after acetylation, two isomeric 1,6-dioxadecalin derivatives 39 and 410 (65%, 3:4 = 8.5:1.5) with good chemo- and stereoselectivity. The structure and stereochemistry of these compounds have been established by extensive spectroscopic analysis and confirmed by X-ray crystallography 11 (Figs. 1 and 2). As observed, both compounds have the same stereochemistry at C-22 but are epimers at C-23. The conformation of the 1,6-dioxadecalin ring systems deserves some comments. In the case of compound 3 with a cis-fusion the rings adopt a double twist boat conformation, while the trans-fused dioxadecalin system in compound 4 exists in crystalline form as a double chair conformation with both methyl groups in axial disposition. A plausible mechanism for the formation of these products is shown in Scheme 3. In the first step, coordination of the aluminum reagent occurs at the tetrahydrofuran oxygen (A) to cleave selectively the C(23)-O bond (B), reduction of the oxonium ion proceeding preferentially with inversion of configuration.
7311
MsO~
.Ms
H
B
A
C
~--OMs , ~OAI(Bui)2 DIBAHB, ~ /AI(Bu)2 I~ l~J
D
8
E Scheme 3
In a second step the formed alkoxy intermediate (C) attacks the C-22 to replace the methanesulfonyl substituent via an SN2 reaction with inversion of configuration to give 3. The minor compound 4 is formed analogously from a reduction that in this case proceeds with retention of configuration. The isomeric methanesulfonate 6 was also treated with DIBAH (8 equiv) in CH2CI 2 at room temperature for 8 h to give, after acetylation, compounds 712 and 813 (62%, 7:8 = 1:1). The structure and stereochemistry of compound 7 were determined by IH and 13C NMR mono- and heteronuclear studies. HMBC, COSY, ROESY and nOe experiments were utilized. The selected ROESY correlations, shown by arrows in Scheme 2, are in good agreement with the proposed structure of cis-l,6-dioxadecalin with all the hydrogens at C-16, C-17, C-22 and C-23, and the methyl groups at C-20 and C-25 on the t~ side of the molecule. Compound 7 is formed by a mechanism similar to that proposed for 3 and 4, via a spiroacetal reduction with retention of configuration. The 1H NMR spectrum of compound 8 clearly indicates the presence of an isopropyl group and hence the reduction of the O-C(26) bond. The observed coupling constants of the low field protons at C-22 and C-23 are in good agreement with those calculated over a minimized structure and indicate that the reaction proceeded with inversion of configuration at C-23 and retention at C-22. The formation of compound 8, the stereochemistry of which was confirmed by a nOe experiment, can be explained by transesterification of intermediate (D) (Scheme 3) and subsequent reduction with an excess of DIBAH of the methylsulfonate (E). We believe that this study illustrates a new methodology for the synthesis of 1,6-dioxadecalins. The method should also find application in the construction of other ring systems of this type. Further work in order to examine this possibility and the generality of these results is under way and will be reported in due course.
Acknowledgement: This work was supported by the Investigation Programme n ° PB93-0171 of the Direcci6n General de Investigaci6n Cientffica y T6cnica. A. M. thanks the Ministerio de Educaci6n y Ciencia, Spain, for a fellowship.
7312
1. Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 189%1909, 2. Murata, M.; Iwashita, T.; Yokoyama, A.; Sasaki, M.; Yasumoto. T. J. Am. Chem. Soc. 1992, 114, 6594-6594. Murata, M.; Naoki, H.; Iwashita, T.; Matsunaga, S.; Sasaki, M.; Yokoyama, A.; Yasumoto. T. Z Am. Chem. Soc. 1993, 115, 2060-2062. Sasaki, M.; Nonomura, T.; Murata, M.; Tachibana, K. Tetrahedron Len. 1994, 35, 5023-5026. 3. Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.; Tanaka, J.; Okumura, Y.; Hirata, Y. J. Am. Chert Soc. 1985, 107, 4796-4798. Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701-710. 4. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162-3164. Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F. P. J. T.; Tiebes, J.; Sato, M.; Untersteller, E.; Xiao, X. -Y. J. Am. Chem. Soc. 1995, 117, 1171-1172. Nicolaou, K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J. Sato, M.; Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173-1174 and references cited. 5. Mart/n, A.; Salazar, J. A.; Su~ez, E. Tetrahedron Lett. 1995, 36, 4489-4492. 6. Vaillancourt, V.; Praft, N. E.; Perron, F.; Albizati, K. F. In The Total Synthesis of Natural Products; Vol. 8; ApSimon, J., Ed.; Wiley: New York, 1992; p 533. Perron, F.; Albizati, K. F, Chem. Rev+ 1989, 89, 1617-1661. Boivin, T. L. B. Tetrahedron 1987, 43, 3309-3362. 7. Pettit, G. R.; Albert, A. H.; Brown, P../. Am. Chem. Soc. 1972, 94, 8095-8099. Oikawa, M.; Oikawa, H.; Ichihara, A. Tetrahedron Len. 1993, 34, 4797-4800. Oikawa, H.; Oikawa, M.; Ichihara, A.; Kobayashi, K.; Uramoto, M. Tetrahedron Letr 1993, 34, 5303-5306. Zhao, Y. -b.; Albizati, K. F. Tetrahedron Lett. 1993, 34, 575-578. Oikawa, M.; Oikawa, H.; Ichihara, A. Tetrahedron 1995, 51, 6237-6254. 8. Hernfindez, R.; Marrero-Tellado, J. J.; Prout, K.; Su~ez, E. J. Chem. Soc., Chem. Commun. 1992, 275-277. 9. Compound 3: m.p. 166-169 °C (MeOH), [~t]D -57° (CHCI3); IR (CHCI3) Vmax 1732, 1245 cm-l; IH NMR (400 MHz, C6D6) 5I-I 0.79 (3H, d, J 6.6 Hz, 27-H3), 0.89 (3H, s, 19-H3), 0.91 (3H, s, 18-H3), 1.23 (3H, d, J 6.8 Hz, 21-H3), 1.75 (3H, s, AcO), 3.10 (IH, dd, J4.7, 2.1 Hz, 22-H), 3.33 (IH, dd, J 10.2, 8.0 Hz, 26-H), 3.5l (1H, dd, J 10.2, 6.7 Hz, 26-H), 3.72 (1H, ddd, J 7.6, 7.6, 4.8 Hz, 23-H), 4.38 (IH, m, 16-H), 4.83 (1H, m, 3-H), 5.29 (IH, m, 6-H); 13C NMR (50.3 MHz, CDC13) iSC inter alia 170.50 (AcO), 139.66 (C-5), 122.39 (C-6), 75.64 (d), 73,90 (C-3), 72.94 (d), 72.24 (C-26), 70.82 (d); MS m/z 456 (M+, 1%), 396.30466 (M+-AcOH). 10. Compound 4: m.p. 171-176 °C (MeOH); IR (CC14) Vmax 1736, 1246 cm-l; IH NMR (200 MHz, CDCI3) ~n 0.89 (3H, s, 18-H3), 1.04 (3H, s, 19-H3), 1.09 (3H, d, J 7.0 Hz), 1.10 (3H, d, J 7.2 Hz), 2.02 (3H, s, AcO), 3.25 (1H, dd, J 9.7, 5.7 Hz, 22-H), 3.45 (1 H, ddd, J 10.6, 9.7, 4.7 Hz, 23-FI), 3.56 (1 H, dd, J 11.8, 2.1 Hz, 26-H), 3.65 (IH, d, J 11.2, 26-H), 4.25 (1 H, m, 16-H), 4.60 (IH, m, 3-H), 5.36 (IH, m, 6-H); 13CNMR (50.3 MHz, CDCI3) 8(: inter alia 170.53 (AcO), 139.81 (C-5), 122.37 (C-6), 79.44 (d), 75,59 (d), 73.88 (C-3), 72.63 (26-C), 65.38 (d); MS m/z 455 (M+-I, 1%), 396.30432 (M+-AcOH, 100%). 11. The data were measured an a Philips PW-1100 four-circle automatic diffractometer operating with Cu Ka radiation (~, = 1.5418/~) monochromated by graphite. Crystal data for 3: C29H4404, orthorhombic, space group P21212h Z = 4, a = 34.049, b = 10.967, c = 7.046 /~, 13 = 90.0°. Crystal data for 4: C29H,IzO4, monoclinic, space group P21, Z = 2, a = 14.290, b = 10.058, c = 9.423/~, ~ = 100.17 °. The coordinates can be obtained, on request, from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK. 12. Compound 7: m.p. 157-160 °C (MeOH), [Ct}D-35 ° (CHCI3); IR (CCIa) Vmax 1735, 1246 cm-l; IH NMR (400 MHz, C6D6) 8H 0.85 (3H, s, 18-H3), 0.87 (3H, d, J 6.2 Hz, 27-H3), 0.88 (3H, s, 19-H3), 1.23 (3H, d, J 7.2 Hz, 21-H3), 1.75 (3H, s, AcO), 3.35 (IH, dd, J 8.3, 8.2 Hz, 26-H), 3.82 (IH, dd, J 7.4, 7.4 Hz, 26-H), 3.92 (1H, ddd, J 7.9, 7.9, 2.2 Hz, 23-H), 4.00 (1H, dd, J 7.7, 2.2 Hz, 22-H), 4.83 (2H, m, 3-H, 16-H), 5.27 (IH, m, 6-H); 13C NMR (50.3 MHz, CDCI3) 8(: inter alia 170.50 (AcO), 139.61 (C-5), 122.40 (C-6), 86.77 (C-22), 83.32 (C-16), 80.13 (C-23), 74.60 (C-26), 73.86 (C-3); MS m/z 456 (M÷, 1%), 396.30383 (M+-AcOH). 13. Compound 8: m.p. 157.5-160 °C (MeOH), [Ot]D-42° (CHC13); IR
(CCI4)Vmax 1742,
1249 cm-l;
IH NMR (200 MHz, C6D6)
8H 0.78 (3H, s, 18-H3), 0.87 (3H, s, 19-H3), 0.92 (3H, d, J 6.4 Hz), 0.93 (3H, d, J 7.1 Hz), 1.04 (3H, d, J 6.4 Hz), 1.75 (3H, s, AcO), 1.82 (3H, s, AcO), 4.06 (IH, dd, J 6.5, 6.5 Hz, 22-H), 4.71 (IH, m, 16-H), 4.84 (IH, m, 3-H), 5.26 (1H, m, 6-H), 5.40 (1H, m, 23-H); 13C NMR (50.3 MHz, CDCI3) 8c inter alia 170.57 (AcO), 170.52 (AcO), 139.67 (C-5), 122.34 (C-6), 84.82 (d), 83.22 (d), 73.83 (C-3), 72.48 (d), MS m/z 501 (M++I, 4%), 440 (M+-AcOH).
(Received in UK 30 June 1995; revised 2 August 1995; accepted 4 August 1995)
Pergamon
Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(95)01472-1
Cis- and Trans-Fused Di-Tetrahydropyrans by Rearrangement
of Steroidal Spiroacetals Rosa L. Dorta, Raimundo Freire, Angeles Martfn, Ernesto Su~ez* Institutode Productos Naturales y Agrobiologfadel C.S.I.C., Carretera de La Esperanza3, 38206-LaLaguna, Tenerife,Spain Thierry Prang6 L.U.R.E., Universit6Paris-Sud,Paris, 91405 ORSAY, Cedex, France
Abstract: A new method for the synthesis of steroidal cis- and trans-fused di-tetrahydropyrans (1,6-dioxadecalins ) by reduction with DIBAH of derivatives of 1,6-dioxaspiro[4.5 ]decan-l O-yl methanesulfonate is described.
Many secondary metabolites from a large variety of natural sources exhibit a 1,6-dioxadecalin rings system in their structures. 1 In more of the cases the rings of this system are trans-fused (brevetoxins, ciguatoxins, gambieric acids, etc.) but some examples of cis-fused rings can be found in maitotoxin2 (rings L/M and N/O) and the halichondrins.3 The important biological activity of such compounds and the chemical complexity of their structures have generated a great interest amongst chemists and biologists.4
H
Scheme 1 H
We have recently described the preparation of chiral spiroacetals using an intramolecular hydrogen abstraction reaction promoted by alkoxy radicals. 5 Spiroacetals are also substructures of many secondary metabolites with interesting biological activities and hence the goal of considerable synthetic work. 6 During this study we envisaged that rearrangement of 0t-hydroxy-spiroacetals to a 1,6-dioxadecalin system can take place as shown in Scheme 1, if we were able to achieve the reduction of the spiroacetal7 with good chemoand stereoselectivity and also transform the hydroxyl into a good leaving group. In theory all possible isomers of the 1,6-dioxadecalin system can be obtained by using this methodology provided we can change the stereochemistry of the reduction and that of the leaving group. As models we have prepared steroidal methanesulfonates 2 and 6 from alcohols 1 and 5 respectively (Scheme 2), resulting from the reduction with NaBH 4 of the corresponding ketone which in turn can be obtained by Lewis acid-mediated rearrangement of 23-oxo-diosgenin.8 7309
13113
OR
o.o-
1R=H 2R=Ms
3
4
7
8
OR
5R=H 6R=Ms
Scheme 2
Figure 1. X-Ray of compound 3
Figure 2. X-Ray of compound 4
The methanesulfonate 2 was reduced with DIBAH (7 equiv) in CH2CI2 at room temperature for 2.5 h to give, after acetylation, two isomeric 1,6-dioxadecalin derivatives 39 and 410 (65%, 3:4 = 8.5:1.5) with good chemo- and stereoselectivity. The structure and stereochemistry of these compounds have been established by extensive spectroscopic analysis and confirmed by X-ray crystallography 11 (Figs. 1 and 2). As observed, both compounds have the same stereochemistry at C-22 but are epimers at C-23. The conformation of the 1,6-dioxadecalin ring systems deserves some comments. In the case of compound 3 with a cis-fusion the rings adopt a double twist boat conformation, while the trans-fused dioxadecalin system in compound 4 exists in crystalline form as a double chair conformation with both methyl groups in axial disposition. A plausible mechanism for the formation of these products is shown in Scheme 3. In the first step, coordination of the aluminum reagent occurs at the tetrahydrofuran oxygen (A) to cleave selectively the C(23)-O bond (B), reduction of the oxonium ion proceeding preferentially with inversion of configuration.
7311
MsO~
.Ms
H
B
A
C
~--OMs , ~OAI(Bui)2 DIBAHB, ~ /AI(Bu)2 I~ l~J
D
8
E Scheme 3
In a second step the formed alkoxy intermediate (C) attacks the C-22 to replace the methanesulfonyl substituent via an SN2 reaction with inversion of configuration to give 3. The minor compound 4 is formed analogously from a reduction that in this case proceeds with retention of configuration. The isomeric methanesulfonate 6 was also treated with DIBAH (8 equiv) in CH2CI 2 at room temperature for 8 h to give, after acetylation, compounds 712 and 813 (62%, 7:8 = 1:1). The structure and stereochemistry of compound 7 were determined by IH and 13C NMR mono- and heteronuclear studies. HMBC, COSY, ROESY and nOe experiments were utilized. The selected ROESY correlations, shown by arrows in Scheme 2, are in good agreement with the proposed structure of cis-l,6-dioxadecalin with all the hydrogens at C-16, C-17, C-22 and C-23, and the methyl groups at C-20 and C-25 on the t~ side of the molecule. Compound 7 is formed by a mechanism similar to that proposed for 3 and 4, via a spiroacetal reduction with retention of configuration. The 1H NMR spectrum of compound 8 clearly indicates the presence of an isopropyl group and hence the reduction of the O-C(26) bond. The observed coupling constants of the low field protons at C-22 and C-23 are in good agreement with those calculated over a minimized structure and indicate that the reaction proceeded with inversion of configuration at C-23 and retention at C-22. The formation of compound 8, the stereochemistry of which was confirmed by a nOe experiment, can be explained by transesterification of intermediate (D) (Scheme 3) and subsequent reduction with an excess of DIBAH of the methylsulfonate (E). We believe that this study illustrates a new methodology for the synthesis of 1,6-dioxadecalins. The method should also find application in the construction of other ring systems of this type. Further work in order to examine this possibility and the generality of these results is under way and will be reported in due course.
Acknowledgement: This work was supported by the Investigation Programme n ° PB93-0171 of the Direcci6n General de Investigaci6n Cientffica y T6cnica. A. M. thanks the Ministerio de Educaci6n y Ciencia, Spain, for a fellowship.
7312
1. Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 189%1909, 2. Murata, M.; Iwashita, T.; Yokoyama, A.; Sasaki, M.; Yasumoto. T. J. Am. Chem. Soc. 1992, 114, 6594-6594. Murata, M.; Naoki, H.; Iwashita, T.; Matsunaga, S.; Sasaki, M.; Yokoyama, A.; Yasumoto. T. Z Am. Chem. Soc. 1993, 115, 2060-2062. Sasaki, M.; Nonomura, T.; Murata, M.; Tachibana, K. Tetrahedron Len. 1994, 35, 5023-5026. 3. Uemura, D.; Takahashi, K.; Yamamoto, T.; Katayama, C.; Tanaka, J.; Okumura, Y.; Hirata, Y. J. Am. Chert Soc. 1985, 107, 4796-4798. Hirata, Y.; Uemura, D. Pure Appl. Chem. 1986, 58, 701-710. 4. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162-3164. Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F. P. J. T.; Tiebes, J.; Sato, M.; Untersteller, E.; Xiao, X. -Y. J. Am. Chem. Soc. 1995, 117, 1171-1172. Nicolaou, K. C.; Rutjes, F. P. J. T.; Theodorakis, E. A.; Tiebes, J. Sato, M.; Untersteller, E. J. Am. Chem. Soc. 1995, 117, 1173-1174 and references cited. 5. Mart/n, A.; Salazar, J. A.; Su~ez, E. Tetrahedron Lett. 1995, 36, 4489-4492. 6. Vaillancourt, V.; Praft, N. E.; Perron, F.; Albizati, K. F. In The Total Synthesis of Natural Products; Vol. 8; ApSimon, J., Ed.; Wiley: New York, 1992; p 533. Perron, F.; Albizati, K. F, Chem. Rev+ 1989, 89, 1617-1661. Boivin, T. L. B. Tetrahedron 1987, 43, 3309-3362. 7. Pettit, G. R.; Albert, A. H.; Brown, P../. Am. Chem. Soc. 1972, 94, 8095-8099. Oikawa, M.; Oikawa, H.; Ichihara, A. Tetrahedron Len. 1993, 34, 4797-4800. Oikawa, H.; Oikawa, M.; Ichihara, A.; Kobayashi, K.; Uramoto, M. Tetrahedron Letr 1993, 34, 5303-5306. Zhao, Y. -b.; Albizati, K. F. Tetrahedron Lett. 1993, 34, 575-578. Oikawa, M.; Oikawa, H.; Ichihara, A. Tetrahedron 1995, 51, 6237-6254. 8. Hernfindez, R.; Marrero-Tellado, J. J.; Prout, K.; Su~ez, E. J. Chem. Soc., Chem. Commun. 1992, 275-277. 9. Compound 3: m.p. 166-169 °C (MeOH), [~t]D -57° (CHCI3); IR (CHCI3) Vmax 1732, 1245 cm-l; IH NMR (400 MHz, C6D6) 5I-I 0.79 (3H, d, J 6.6 Hz, 27-H3), 0.89 (3H, s, 19-H3), 0.91 (3H, s, 18-H3), 1.23 (3H, d, J 6.8 Hz, 21-H3), 1.75 (3H, s, AcO), 3.10 (IH, dd, J4.7, 2.1 Hz, 22-H), 3.33 (IH, dd, J 10.2, 8.0 Hz, 26-H), 3.5l (1H, dd, J 10.2, 6.7 Hz, 26-H), 3.72 (1H, ddd, J 7.6, 7.6, 4.8 Hz, 23-H), 4.38 (IH, m, 16-H), 4.83 (1H, m, 3-H), 5.29 (IH, m, 6-H); 13C NMR (50.3 MHz, CDC13) iSC inter alia 170.50 (AcO), 139.66 (C-5), 122.39 (C-6), 75.64 (d), 73,90 (C-3), 72.94 (d), 72.24 (C-26), 70.82 (d); MS m/z 456 (M+, 1%), 396.30466 (M+-AcOH). 10. Compound 4: m.p. 171-176 °C (MeOH); IR (CC14) Vmax 1736, 1246 cm-l; IH NMR (200 MHz, CDCI3) ~n 0.89 (3H, s, 18-H3), 1.04 (3H, s, 19-H3), 1.09 (3H, d, J 7.0 Hz), 1.10 (3H, d, J 7.2 Hz), 2.02 (3H, s, AcO), 3.25 (1H, dd, J 9.7, 5.7 Hz, 22-H), 3.45 (1 H, ddd, J 10.6, 9.7, 4.7 Hz, 23-FI), 3.56 (1 H, dd, J 11.8, 2.1 Hz, 26-H), 3.65 (IH, d, J 11.2, 26-H), 4.25 (1 H, m, 16-H), 4.60 (IH, m, 3-H), 5.36 (IH, m, 6-H); 13CNMR (50.3 MHz, CDCI3) 8(: inter alia 170.53 (AcO), 139.81 (C-5), 122.37 (C-6), 79.44 (d), 75,59 (d), 73.88 (C-3), 72.63 (26-C), 65.38 (d); MS m/z 455 (M+-I, 1%), 396.30432 (M+-AcOH, 100%). 11. The data were measured an a Philips PW-1100 four-circle automatic diffractometer operating with Cu Ka radiation (~, = 1.5418/~) monochromated by graphite. Crystal data for 3: C29H4404, orthorhombic, space group P21212h Z = 4, a = 34.049, b = 10.967, c = 7.046 /~, 13 = 90.0°. Crystal data for 4: C29H,IzO4, monoclinic, space group P21, Z = 2, a = 14.290, b = 10.058, c = 9.423/~, ~ = 100.17 °. The coordinates can be obtained, on request, from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK. 12. Compound 7: m.p. 157-160 °C (MeOH), [Ct}D-35 ° (CHCI3); IR (CCIa) Vmax 1735, 1246 cm-l; IH NMR (400 MHz, C6D6) 8H 0.85 (3H, s, 18-H3), 0.87 (3H, d, J 6.2 Hz, 27-H3), 0.88 (3H, s, 19-H3), 1.23 (3H, d, J 7.2 Hz, 21-H3), 1.75 (3H, s, AcO), 3.35 (IH, dd, J 8.3, 8.2 Hz, 26-H), 3.82 (IH, dd, J 7.4, 7.4 Hz, 26-H), 3.92 (1H, ddd, J 7.9, 7.9, 2.2 Hz, 23-H), 4.00 (1H, dd, J 7.7, 2.2 Hz, 22-H), 4.83 (2H, m, 3-H, 16-H), 5.27 (IH, m, 6-H); 13C NMR (50.3 MHz, CDCI3) 8(: inter alia 170.50 (AcO), 139.61 (C-5), 122.40 (C-6), 86.77 (C-22), 83.32 (C-16), 80.13 (C-23), 74.60 (C-26), 73.86 (C-3); MS m/z 456 (M÷, 1%), 396.30383 (M+-AcOH). 13. Compound 8: m.p. 157.5-160 °C (MeOH), [Ot]D-42° (CHC13); IR
(CCI4)Vmax 1742,
1249 cm-l;
IH NMR (200 MHz, C6D6)
8H 0.78 (3H, s, 18-H3), 0.87 (3H, s, 19-H3), 0.92 (3H, d, J 6.4 Hz), 0.93 (3H, d, J 7.1 Hz), 1.04 (3H, d, J 6.4 Hz), 1.75 (3H, s, AcO), 1.82 (3H, s, AcO), 4.06 (IH, dd, J 6.5, 6.5 Hz, 22-H), 4.71 (IH, m, 16-H), 4.84 (IH, m, 3-H), 5.26 (1H, m, 6-H), 5.40 (1H, m, 23-H); 13C NMR (50.3 MHz, CDCI3) 8c inter alia 170.57 (AcO), 170.52 (AcO), 139.67 (C-5), 122.34 (C-6), 84.82 (d), 83.22 (d), 73.83 (C-3), 72.48 (d), MS m/z 501 (M++I, 4%), 440 (M+-AcOH).
(Received in UK 30 June 1995; revised 2 August 1995; accepted 4 August 1995)