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Model studies towards a biomimetic synthesis of keramaphidin B and halicyclamine A
Tetrahedron Letters, Vol. 36, No. 35, pp. 6231-6234, 1995 Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
Pergamon 0040-4039(95)01270-2
Model Studies towards a Biomimetic Synthesis of Keramaphidin B and Halicyclamine A Laurent Gil, Xavier Baucherel, Marie-Th~r~se Martin, Christian Marazano* and Bhupesh C. Das.* lnstitut de Chiraie des Substances Naturelles, C 2VR.S., 91198 Gif-sur-Yvette , France
Abstract: As a model for condensation reactions of macroeycles of type 1, which are possibly implicated in the biosynthesis of a number of new alkaloids recently extracted from sponges, we now report that treatment of dihydmpyridinium salt 13 with Iriethylamine in dichloromethane gave, after reduction with sodium borohydride, adducts 15 and 16 in 25% and 7% isolated yields, respectively. The slructures of these adducts are identical to the core slruetmes of keramaphidin B, a biogenetic precursor of manzamines, and halicyclamine A
Bis-dihydropyridine macrocycles of type 1 possessing various 3-alkyl chains linking the two
heterocycles are very likely to be implicated in the biosynthesis of an increasing number of marine alkaloids recently extracted from different sponges. Such a macrocycle was first postulated by Baldwin and Whitehead 1 as the origin of a key pentacyclic intermediate in the biosynthesis of manzamines A and B, a new class of cytotoxic alkaloids. Remarkably, the occurrence of this predicted intermediate almost in its entirety became apparent some time later through the isolation of keramaphidin B 2 and its hydroxylated analog ingenamine. 3 These latter compounds, resulting from an intramolecular cycloaddition reaction of I and possessing a core isoquinuclidine framework, belong to a class of alkaloids which include ingamines A and B 4 and xestocyclamine A. 5 In addition, madangamine A was postulated as a rearrangement product of an ingamine B isomer.6 On the other hand, halicyclamine A 7 is a representative of yet another family of alkaloids which could also be derived from a macrocycle 1. Closely related to this last family is sarain 1,8 and possibly sarain A.9,10
=>
Halicycl~Tline A
Keramaphidin B
Condensation reactions (Scheme 1) of 3-substituted 5,6-dihydropyridinium salts 2 with 1,6dihydropyridines 3, both species implied in the chemistry of macrocycles 1, can in principle lead to two primary adducts 4 and 5 if one considers that the position 5 in 3 is more reactive than the substituted position 3. Adduct 5 can further cyclize to give isoquinuclidine 6 which thus formally results from a cycloaddition reaction in which the 3,4-double bond in 2 acts as a dienophile, while dihydropyridine 3 acting as a diene. These reactions can be reversible allowing a thermodynamic equilibrium to be attained. Finally, a competitive but irreversible oxido-reductive process (dismutation) can lead to pyridinium salt 7 and tetrahydropyridine S. Reduction of the overall mixture resulting from reactions between species 2 and 3 should thus provide monomeric tetrahydropyridine 8 and ~ree types of diastereoisomeric adducts: one resulting from reduction of 4, a second type 9 (four diastereoisomers) from adduets $ and the third 10 via intermediate 6. No product corresponding to 6231
6232
the initially formed adducts 4 has so far bccn isolated from sponges while one ofdiastereoisomers 9 is found in the core skeleton o f halicyclamine A whereas the endo adduct 10 is the core skeleton o f keramaphidin B. 5 6
4
I R H-(H
>
+
9
I
I
R
R
2
3
7
8
~"N~R H-
+ )
I
R
I
I
R
5
R
6
~"N'''R
R
.
10
Scheme 1 The challenging problem now is to control reactions depicted in Scheme I in order to design short mutes to a number of these natural macrocyclic alkaloids. As a first concrete evidence in favor of their elegant proposal on the origin of manzamines, Baldwin's group recently reported I I that treatment of salt 2 (R = Et) in a pH 8.3 buffer during 18 h, followed by NaBH4 reduction, gave the tetrahydropyridine 8 (R = Et) as the main product along with the adduct I0 (R = Et) in 10% yield. Our own contribution in this field I0 consisted in disclosing conditions for deprotonating salts of type 2 to give dihydropyridines 3 which were unstable at the reaction temperature, but could be trapped with common dienophiles. As an extension of our initial studies towards generation of species 1,12 we now report further model reactions summarized in Scheme 2. The methoxy adduct 12 was obtained in 80% yield according to our reported protocoll0,12 by quenching the salt U , obtained by the Polonovski-Potier procedure, with sodium methoxide. Treatment of this product with one equivalent of camphorsulphonic acid (CSAH) gave salt 13 in quantitative yield. The methanol liberated during this reaction was eliminated under reduced pressure. We preferred this procedure rather than to use directly trifluoroacetate salts I I , issuing from the Polonovski-Potier reaction, which remained contaminated with trifluoroacetic acid. We thus found that treatment of salt 13 with 0.6 equivalent of triethylamine in dry CH2C12 during two hours, followed by NaBH4 reduction in isopropanol, gave tetrahydropyridine 14 in 40% yield along with two adducts 15 and 16 isolated in 25% and 7% yields, respectively, after chromatography on alumina. The remaining products were essentially polar dimers whose structures are not yet elucidated. Characterization of the products formed were facilitated by GC analysis on a capillary column, with eicosane as an internal standard, and GC-MS measurements. Kinetic studies (IH-NMR of the reaction mixture conducted in CDCI3 and subsequent GC analysis after reduction) showed rapid formation of the cycloadduct corresponding to 6 (R = n-hexyl; olefinic H-4 at 8 6.0 ppm) which reached its peak after two hours and then decreased suggesting a reversible equilibrium among species 2, 3, 5 and 6 ((R = n-hexyl) leading finally to the irreversible accumulation of pyridinium salt 7 (R = n-bexyl) and tetrahydropyridine 8 (R = n-hexyl; 14) which were also formed during the f'krStminutes of the reaction and were easily identified by the IH-NMR spectra. Interestingly, compound 15 was already found to be present in small amount before the NaBH4 reduction suggesting a reduction of iminium species 6 (R = n-hexyl) by dihydropyridine 3 (R = n-hexyl). Structures of adducts 15 and 16 were established by NMR and mass spectroscopy. 13
6233
OMe
Me
Me
~
11
,.~
12
Me
i,,,
Me
13
14
Me
Me
e
Me
÷
~ "v~''fMe
Me
Me
15
M.
n
H
16
Scheme 2 Data for adduct 15, including nOe's, are in full agreement with the analoguous compound already described by Baldwin et al. 11 Compound 16 displayed characteristics nOe's (double arrows in structure 16), suggesting that the major conformer in solution is arranged, as expected, in such a way that the C5-H bond practically eclipsed the C9-C14 bond, thus minimizing steric interactions. The observed hoe (not shown in structure 16) between H- 12ax and H- 10 is consistent with a chair conformation of the piperidine ring bearing an axial H-10. 26
Me
13
15
7 Me 14
18 15
19 Me 20
Me b 14 ~
k
"'~r~ / ,~H 16
The diastereoisomeric arrangement at C5 is deduced from nods shown in 16. In addition, a coupling constant of 9.4 Hz between H-5 and H-6ax indicates that H-5 is axial, the tetrahydropyridine ring being in a pseudo-chair geometry. Additional nods between H-2ax, H-6ax and 2H-15 confh"med these assignments and the orientation of the nitrogen lone-pair.
Figure 1. Chem 3D stereoview of the lowest energy conformer of 16 found using SYBYL.
6234
Further evidence in favor of structure 16 was provided by modelisation experiments using the SYBYL program. The lowest energy conformer found, represented in Figure I, fully agrees with NMR data. Interestingly, adducts 15 and 16 showed IC50 values 0.51.tg/mL and ll.tg/mL, respectively, against KB ceils suggesting that the presence of a macrocycle is probably not essential for significant cytotoxicity. Acknowledgements: W e thank Marie-Annick Billion for G C - M S experiments. References and Notes: 1- Baldwin, J. E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33, 2059-2062. 2- Kobayashi, J.; Tsuda, M.; Kawasaki, N.; Matsumoto, K.; Adachi, T. Tetrahedron Lett. 1994, 35, 43834386. 3- Kong, F.; Andersen, R. J.; Allen, T. M. Tetrahedron Lett. 1994, 35, 1643-1646. 4- Kong, F.; Andersen, R. J.; Allen, T. M. Tetrahedron 1994, 50, 6137-6144. 5- Rodriguez, J.; Crews, P. Tetrahedron Letters 1994, 35, 4719-4722. 6- Kong, F.; Andersen, R. J.; Allen, T. M. J. Am. Chem. Soc. 1994, 116, 6007-6008. 7- Jaspars, M.; Pasupathy, V.; Crews, P. J. Org. Chem. 1994, 59, 3253-3255. 8- Cimino, G.; De Stefano, S.; Scognamiglio, G.; Sodano, G.; Trivellone, E. Bull. Soc. Chim. Belg. 1986, 95, 783-800. 9- Cimino, G.; Mattia, C. A.; Mazzarella, L.; Puliti, R.; Scognamiglio, G.; Spinella, A.; Trivellone, E. Tetrahedron 1989, 45, 3863-3872. 10- Gil, L.; Gateau-Olesker, A.; Marazano, C.; Das, B. C. Tetrahedron Lett. 1995, 36, 707-710. 11- Baldwin, J. E.; Claridge, T. D. W.; Heupel, F. A.; Whitehead, R. C. Tetrahedron Lett. 1994, 35, 78297832. 12- Gil, L.; Gateau-Olesker, A.; Wong, Y.-S.; Chernatova, L.; Marazano, C.; Das, B. C. Tetrahedron Lett. 1995, 36, 2059-2062. 13- Selected spectroscopic data: Adduct 15: HRMS (EI): calcd for C24H44N2 m/z 360.3504, obsd m/z 360.3495. NMR data in CDCI3 (100 MHz for 13C/400 MHz for 1H) [Cn °, 8 1H (8 13(2)]: C2, 2.45, d, J= 1.8 Hz (67.1); C3 (139.9); C4, 5.75, ddd, J= 1.7, 1.7, 5.4 Hz (121.2); C5, 2.12, m (38.4); C6, 2.90(ax), dd, J= 2.0, 9.3 Hz, 1.67(eq), dd, J= 2.8, 9.3 Hz (55.4); C8, 2.14, bd, J= 11.1 Hz, 2.07, bd, J= 11.1 Hz (56.8); C9 (42.8); CI0, 1.14, m (41.6); CI1, 1.20(eq), m, 1.42(ax) (27.1); C12, 2.41(eq), m, 2.66(ax), ddd, J= 4.1, 11.1, 11.1 Hz (49.8); C13, 1.77,d, J= 1.8 Hz (23.4); C14, 1.26, s (28.8); C15, 2.35(a), m, 2.08('o), m (58.1); C16 (28.7); C17 (27.5*); C18 (32.0); C19 (22.8); C20, 0.84, t, J= 7 Hz (14.2); C21, 2.369, m (59.8); C22 (27.0*); C23 (27.1"); C24 (32.0); C25 (22.8); C26, 0.84, t, J= 7 Hz (14.2). Adduet 16: HRMS (El): calcd for C24H46N2 m/z 362.3660, obsd m/z 362.3657. NMR data in CDCI3 (100 MHz for 13C/ 400 MHz for 1H) [Cn °, 5 1H (8 13C)]: C2, 2.54(ax), bd, J= 16 Hz, 2.99(eq),bd, J= 16 Hz (57.1); C3 (132.4); C4, 5.12, bs (124.7); C5, 2.73, m (35.8); C6, 1.95(ax), dd, J= 9.4, 9.4 Hz, 2.67(eq), dd, J= 5.6, 9.4 Hz (50.6); C8, 1.53(ax), m, 2.85(eq), dd, J= 1.8, 7.3 Hz (62.7); C9, 1.57, m (32.8); CI0, 1.03,m (46.4); C I I , 1.40(ax), m , 1.53(eq), m (26.3); C12, 1.77(ax), ddd, J= 2.7, 11.5, 11.5 Hz, 2.90(eq), din, J= 11.5 (54.8); C13, 1.65, bs (21.0); C14, 0.85, d, J-- 6.5 Hz (17.0); C15, 2.36, m (58.8); C16, 1.55, m (27.0*); C17, 1.30, m (27.4*); C18 (31.8); C19 (22.6); C20, 0.85, t, J= 7 I-Iz (14.0); C21, 2.25, m (59.2); C22, 1.50, m (27.0*); C23, 1.30, m (27.4*); C24 (31.8); C25 (22.6); C26, 0.85, t, J= 7 Hz (14.0). * These assignments may be interchanged.
(Received in France 31 May 1995; accepted 5 July 1995)
Pergamon 0040-4039(95)01270-2
Model Studies towards a Biomimetic Synthesis of Keramaphidin B and Halicyclamine A Laurent Gil, Xavier Baucherel, Marie-Th~r~se Martin, Christian Marazano* and Bhupesh C. Das.* lnstitut de Chiraie des Substances Naturelles, C 2VR.S., 91198 Gif-sur-Yvette , France
Abstract: As a model for condensation reactions of macroeycles of type 1, which are possibly implicated in the biosynthesis of a number of new alkaloids recently extracted from sponges, we now report that treatment of dihydmpyridinium salt 13 with Iriethylamine in dichloromethane gave, after reduction with sodium borohydride, adducts 15 and 16 in 25% and 7% isolated yields, respectively. The slructures of these adducts are identical to the core slruetmes of keramaphidin B, a biogenetic precursor of manzamines, and halicyclamine A
Bis-dihydropyridine macrocycles of type 1 possessing various 3-alkyl chains linking the two
heterocycles are very likely to be implicated in the biosynthesis of an increasing number of marine alkaloids recently extracted from different sponges. Such a macrocycle was first postulated by Baldwin and Whitehead 1 as the origin of a key pentacyclic intermediate in the biosynthesis of manzamines A and B, a new class of cytotoxic alkaloids. Remarkably, the occurrence of this predicted intermediate almost in its entirety became apparent some time later through the isolation of keramaphidin B 2 and its hydroxylated analog ingenamine. 3 These latter compounds, resulting from an intramolecular cycloaddition reaction of I and possessing a core isoquinuclidine framework, belong to a class of alkaloids which include ingamines A and B 4 and xestocyclamine A. 5 In addition, madangamine A was postulated as a rearrangement product of an ingamine B isomer.6 On the other hand, halicyclamine A 7 is a representative of yet another family of alkaloids which could also be derived from a macrocycle 1. Closely related to this last family is sarain 1,8 and possibly sarain A.9,10
=>
Halicycl~Tline A
Keramaphidin B
Condensation reactions (Scheme 1) of 3-substituted 5,6-dihydropyridinium salts 2 with 1,6dihydropyridines 3, both species implied in the chemistry of macrocycles 1, can in principle lead to two primary adducts 4 and 5 if one considers that the position 5 in 3 is more reactive than the substituted position 3. Adduct 5 can further cyclize to give isoquinuclidine 6 which thus formally results from a cycloaddition reaction in which the 3,4-double bond in 2 acts as a dienophile, while dihydropyridine 3 acting as a diene. These reactions can be reversible allowing a thermodynamic equilibrium to be attained. Finally, a competitive but irreversible oxido-reductive process (dismutation) can lead to pyridinium salt 7 and tetrahydropyridine S. Reduction of the overall mixture resulting from reactions between species 2 and 3 should thus provide monomeric tetrahydropyridine 8 and ~ree types of diastereoisomeric adducts: one resulting from reduction of 4, a second type 9 (four diastereoisomers) from adduets $ and the third 10 via intermediate 6. No product corresponding to 6231
6232
the initially formed adducts 4 has so far bccn isolated from sponges while one ofdiastereoisomers 9 is found in the core skeleton o f halicyclamine A whereas the endo adduct 10 is the core skeleton o f keramaphidin B. 5 6
4
I R H-(H
>
+
9
I
I
R
R
2
3
7
8
~"N~R H-
+ )
I
R
I
I
R
5
R
6
~"N'''R
R
.
10
Scheme 1 The challenging problem now is to control reactions depicted in Scheme I in order to design short mutes to a number of these natural macrocyclic alkaloids. As a first concrete evidence in favor of their elegant proposal on the origin of manzamines, Baldwin's group recently reported I I that treatment of salt 2 (R = Et) in a pH 8.3 buffer during 18 h, followed by NaBH4 reduction, gave the tetrahydropyridine 8 (R = Et) as the main product along with the adduct I0 (R = Et) in 10% yield. Our own contribution in this field I0 consisted in disclosing conditions for deprotonating salts of type 2 to give dihydropyridines 3 which were unstable at the reaction temperature, but could be trapped with common dienophiles. As an extension of our initial studies towards generation of species 1,12 we now report further model reactions summarized in Scheme 2. The methoxy adduct 12 was obtained in 80% yield according to our reported protocoll0,12 by quenching the salt U , obtained by the Polonovski-Potier procedure, with sodium methoxide. Treatment of this product with one equivalent of camphorsulphonic acid (CSAH) gave salt 13 in quantitative yield. The methanol liberated during this reaction was eliminated under reduced pressure. We preferred this procedure rather than to use directly trifluoroacetate salts I I , issuing from the Polonovski-Potier reaction, which remained contaminated with trifluoroacetic acid. We thus found that treatment of salt 13 with 0.6 equivalent of triethylamine in dry CH2C12 during two hours, followed by NaBH4 reduction in isopropanol, gave tetrahydropyridine 14 in 40% yield along with two adducts 15 and 16 isolated in 25% and 7% yields, respectively, after chromatography on alumina. The remaining products were essentially polar dimers whose structures are not yet elucidated. Characterization of the products formed were facilitated by GC analysis on a capillary column, with eicosane as an internal standard, and GC-MS measurements. Kinetic studies (IH-NMR of the reaction mixture conducted in CDCI3 and subsequent GC analysis after reduction) showed rapid formation of the cycloadduct corresponding to 6 (R = n-hexyl; olefinic H-4 at 8 6.0 ppm) which reached its peak after two hours and then decreased suggesting a reversible equilibrium among species 2, 3, 5 and 6 ((R = n-hexyl) leading finally to the irreversible accumulation of pyridinium salt 7 (R = n-bexyl) and tetrahydropyridine 8 (R = n-hexyl; 14) which were also formed during the f'krStminutes of the reaction and were easily identified by the IH-NMR spectra. Interestingly, compound 15 was already found to be present in small amount before the NaBH4 reduction suggesting a reduction of iminium species 6 (R = n-hexyl) by dihydropyridine 3 (R = n-hexyl). Structures of adducts 15 and 16 were established by NMR and mass spectroscopy. 13
6233
OMe
Me
Me
~
11
,.~
12
Me
i,,,
Me
13
14
Me
Me
e
Me
÷
~ "v~''fMe
Me
Me
15
M.
n
H
16
Scheme 2 Data for adduct 15, including nOe's, are in full agreement with the analoguous compound already described by Baldwin et al. 11 Compound 16 displayed characteristics nOe's (double arrows in structure 16), suggesting that the major conformer in solution is arranged, as expected, in such a way that the C5-H bond practically eclipsed the C9-C14 bond, thus minimizing steric interactions. The observed hoe (not shown in structure 16) between H- 12ax and H- 10 is consistent with a chair conformation of the piperidine ring bearing an axial H-10. 26
Me
13
15
7 Me 14
18 15
19 Me 20
Me b 14 ~
k
"'~r~ / ,~H 16
The diastereoisomeric arrangement at C5 is deduced from nods shown in 16. In addition, a coupling constant of 9.4 Hz between H-5 and H-6ax indicates that H-5 is axial, the tetrahydropyridine ring being in a pseudo-chair geometry. Additional nods between H-2ax, H-6ax and 2H-15 confh"med these assignments and the orientation of the nitrogen lone-pair.
Figure 1. Chem 3D stereoview of the lowest energy conformer of 16 found using SYBYL.
6234
Further evidence in favor of structure 16 was provided by modelisation experiments using the SYBYL program. The lowest energy conformer found, represented in Figure I, fully agrees with NMR data. Interestingly, adducts 15 and 16 showed IC50 values 0.51.tg/mL and ll.tg/mL, respectively, against KB ceils suggesting that the presence of a macrocycle is probably not essential for significant cytotoxicity. Acknowledgements: W e thank Marie-Annick Billion for G C - M S experiments. References and Notes: 1- Baldwin, J. E.; Whitehead, R. C. Tetrahedron Lett. 1992, 33, 2059-2062. 2- Kobayashi, J.; Tsuda, M.; Kawasaki, N.; Matsumoto, K.; Adachi, T. Tetrahedron Lett. 1994, 35, 43834386. 3- Kong, F.; Andersen, R. J.; Allen, T. M. Tetrahedron Lett. 1994, 35, 1643-1646. 4- Kong, F.; Andersen, R. J.; Allen, T. M. Tetrahedron 1994, 50, 6137-6144. 5- Rodriguez, J.; Crews, P. Tetrahedron Letters 1994, 35, 4719-4722. 6- Kong, F.; Andersen, R. J.; Allen, T. M. J. Am. Chem. Soc. 1994, 116, 6007-6008. 7- Jaspars, M.; Pasupathy, V.; Crews, P. J. Org. Chem. 1994, 59, 3253-3255. 8- Cimino, G.; De Stefano, S.; Scognamiglio, G.; Sodano, G.; Trivellone, E. Bull. Soc. Chim. Belg. 1986, 95, 783-800. 9- Cimino, G.; Mattia, C. A.; Mazzarella, L.; Puliti, R.; Scognamiglio, G.; Spinella, A.; Trivellone, E. Tetrahedron 1989, 45, 3863-3872. 10- Gil, L.; Gateau-Olesker, A.; Marazano, C.; Das, B. C. Tetrahedron Lett. 1995, 36, 707-710. 11- Baldwin, J. E.; Claridge, T. D. W.; Heupel, F. A.; Whitehead, R. C. Tetrahedron Lett. 1994, 35, 78297832. 12- Gil, L.; Gateau-Olesker, A.; Wong, Y.-S.; Chernatova, L.; Marazano, C.; Das, B. C. Tetrahedron Lett. 1995, 36, 2059-2062. 13- Selected spectroscopic data: Adduct 15: HRMS (EI): calcd for C24H44N2 m/z 360.3504, obsd m/z 360.3495. NMR data in CDCI3 (100 MHz for 13C/400 MHz for 1H) [Cn °, 8 1H (8 13(2)]: C2, 2.45, d, J= 1.8 Hz (67.1); C3 (139.9); C4, 5.75, ddd, J= 1.7, 1.7, 5.4 Hz (121.2); C5, 2.12, m (38.4); C6, 2.90(ax), dd, J= 2.0, 9.3 Hz, 1.67(eq), dd, J= 2.8, 9.3 Hz (55.4); C8, 2.14, bd, J= 11.1 Hz, 2.07, bd, J= 11.1 Hz (56.8); C9 (42.8); CI0, 1.14, m (41.6); CI1, 1.20(eq), m, 1.42(ax) (27.1); C12, 2.41(eq), m, 2.66(ax), ddd, J= 4.1, 11.1, 11.1 Hz (49.8); C13, 1.77,d, J= 1.8 Hz (23.4); C14, 1.26, s (28.8); C15, 2.35(a), m, 2.08('o), m (58.1); C16 (28.7); C17 (27.5*); C18 (32.0); C19 (22.8); C20, 0.84, t, J= 7 Hz (14.2); C21, 2.369, m (59.8); C22 (27.0*); C23 (27.1"); C24 (32.0); C25 (22.8); C26, 0.84, t, J= 7 Hz (14.2). Adduet 16: HRMS (El): calcd for C24H46N2 m/z 362.3660, obsd m/z 362.3657. NMR data in CDCI3 (100 MHz for 13C/ 400 MHz for 1H) [Cn °, 5 1H (8 13C)]: C2, 2.54(ax), bd, J= 16 Hz, 2.99(eq),bd, J= 16 Hz (57.1); C3 (132.4); C4, 5.12, bs (124.7); C5, 2.73, m (35.8); C6, 1.95(ax), dd, J= 9.4, 9.4 Hz, 2.67(eq), dd, J= 5.6, 9.4 Hz (50.6); C8, 1.53(ax), m, 2.85(eq), dd, J= 1.8, 7.3 Hz (62.7); C9, 1.57, m (32.8); CI0, 1.03,m (46.4); C I I , 1.40(ax), m , 1.53(eq), m (26.3); C12, 1.77(ax), ddd, J= 2.7, 11.5, 11.5 Hz, 2.90(eq), din, J= 11.5 (54.8); C13, 1.65, bs (21.0); C14, 0.85, d, J-- 6.5 Hz (17.0); C15, 2.36, m (58.8); C16, 1.55, m (27.0*); C17, 1.30, m (27.4*); C18 (31.8); C19 (22.6); C20, 0.85, t, J= 7 I-Iz (14.0); C21, 2.25, m (59.2); C22, 1.50, m (27.0*); C23, 1.30, m (27.4*); C24 (31.8); C25 (22.6); C26, 0.85, t, J= 7 Hz (14.0). * These assignments may be interchanged.
(Received in France 31 May 1995; accepted 5 July 1995)