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A biomimetic-like radical approach to furanoditerpenes
Tetrahedron Letters, Vol. 36, No. 17, pp. 2925-2928, 1995 Elsevier Science Ltd Printed in Great Britain 0040-4039/95 $9.50+0.00
Pergamon 0040-4039(95)00433-5
A Biomimetic-Like Radical Approach To Furanoditerpenes PhiHip A. Zoretic*, Zhongqi Shen and Ming Wang ~cnt of Chemistry East CarolinaUniversity Greenville,NC 27858
Anthony A. Ribeiro DukeNMR SpectroscopyCenter Departmentof Radiology DukeUniversityMedicalCent~ Durham,NC 27710
Abstract: A highlystereoselectivcoxidativefree-radicalcyclizationofpolyone9 has beendemonstratedas a one step entryto a complextricaflx~yclicsTnthon10 whichcontainsfivecrucialstemogeniccenters. An entry the spongianand marginatanefuranoditerpeneshas beenrealizedfromsynthon10.
to
A variety of marine natural products I have been isolated from sponges which possess diverse biological activity. In particular the furanoditerpenes, spongiadiol 1, epispongiadiol 2, and isospongiadiol 3, isolated2 fi'om a deep water Caribbean sponge, Spongia sp. Linnaeus, exhibit activity against Herpessimplex virus, type 1 and P388 murine leukemia cells. The spongians 1 and 2 have also been isolated previously from Spongia species 3 collected in the Australian waters. The metabolites,4 marginafuran 4 and marginatone 5, possessing the rare marginatane carbon skeleton, have also been reported.
R1 R2
0.~"~~ OH 1: RI=H,R 2=OH
2: RI=OH,R 2=H
0 HOs.~~
0
OH 3
4:R= CO2H,R 1 =R2=H 5:Rffi CHa,R I = R 2 = O
Recently Kanematsu5 reported a tandem allene Diels-Alder bis-annulationapproach to the spongian skeleton. Herein we would like to communicate an alternative stereoselective biomimetic-
2925
2926
like radical cyclization strategy as a facile entry to the aforementioned natural products. It was anticipated, based on our previous work,6 that oxidative free-radical cyclization of 13-keto ester 9 would introduce stereoselectively five key chiral centers and also generate the necessary C-4 pro-13-hydroxymethylene in synthon 10. The C-14 exocyclic methylene would also provide an entry to both the spongian and marginatane furan ring systems. The synthesis of the targeted 13-ketoester 9 and the construction of the furan ring systems depicted in the spongians and marginatanes are delineated below. Reaction of allyl alcohol 66 with thionyl chloride7(Scheme I) and subsequent chromatography afforded an 87:13 ratio of rearranged allyl chloride 7 and allyl chloride 8. Alkylation of this mixture with the dianion 8 of ethyl 2-methylacetoacetate (generated from one equivalent of Nail followed by one equivalent of n-BuLi) gave I~-keto ester 9, after chromatography. Oxidative free-radical cyclization of 9, as a 0.1M solution in deaerated acetic acid, with a 2:1 molar ratio of Mn(OAc)y2H20 and Cu(OAc)2.H20 at 25 oc for one day under Ar yielded tricyclic keto ester I0 (mp 90-91 oc) in 43% yield. Scheme I
o•
(74%)
H
6
7
8 (66%)~b
1~'43%)
Et02C 10
0
C02Et 9
aSOCL2,CC14,rt; bLiCH2C(O)CMe(Na)CO2Et,THF, HMPA,0 °C, 2.5 hr; then aq. HCI; e2eq. Mn(OAc)3-2H20,1 eq. Cu(OAc)2.H20,de.aeratedHOAc,At, rt, 24 hr. In order to prove the stereochemistry depicted in 10 by NOE studies, a series of HMQC, HMBC and Cosy 2D NMR studies 9 were used to determine the assignment of each proton resonance signal in 10. Utilizing these assignments it was noted that irradiation of the C-10 angular methyl at 1.028 showed an enhancement of the C-2 axial proton (2.948), C-6 axial proton (2.118), C-11axial proton (1.488) and one methyleneoxy proton of the ester at 4.518. Likewise irradiation of the C-8 angular methyl showed an enhancement of the C-13 axial proton (2.308), C-11 axial proton (1.488), C-6 axial proton (2.118) and the C-7 equatorial proton (1.798), thus confirming the relative stereochemistry in 10.
2927
With the stereochemistryin I0 secured,our attentionwas turnedto the constructionof the marginatane and spongian furan ring systems as detailedbelow. Reduction of 10 (Scheme II)with L A H and subsequent dibenzoylationof dio111 (nap 165-166 oc) with benzoyl chlorideand 4 - D M A P in the presence of Et3N gave 12 (mp 193-194 oc). Ozonolysis of 12 and reductionof the resulting Scheme II
O
(94%,73%) RO
EtO2C
(52%) RzO OR 11: R = H
10
12: R = BZ
OBz 13
(88%= d)~ OH
RO
-(82%, OR 15: R = Bz 16: R = H
78%)BzOV ~H v OBz 14
=[.A_l-I,Et20, reflux; ~COC1, 4-DMAP,Et3N,CH2C12,rt, 2 hr; eO3,CH2C12,-78 0C; then Ph3P; dl.5 eq. LDA, THF, -78 °C; then 2.3 eq. of ZnCI2,followedby 2.0 eq. of CHOCH2OT/-IP, -78 °C -> -45 °(2 -> 0 °C ; sat. Nil 4C1; eaq.THF,p-TsOH,62 °(2 - 70 °(2,50 min. ozonide with Ph3P afforded ketone 13 (mp 211-211.5 oC), after chromatography. A direct route to the marginatane furan ring system was realized by modification of Hagiwara's l0 procedure. Thus reaction of the lithium enolate of 13 (generated from LDA at -78 °C) with 2.3 equivalents of ZnC12 followed by aldol condensation of the resulting zinc enolate with 2.0 equivalents of CHOCH2OTHP (-78 oC -> -45 oC -> 0 °C) yielded the 13-hydroxyketones 14, after chromatography. Concomitant hydrolysis of 14 with aqueous THF in the presence ofp-TsOH gave IS (mp 138-138.5 oc) and subsequent hydride reduction of I5 with LAH afforded diol 16 (mp 216-217 oc). A direct route to the 3, 4-disubstituted furan ring system in the spongians was realized as outlined in Scheme HI. Ozonolysis of diol 11 and subsequent reaction of ketone 17 (mp 166-166.5 oC) with acetone in the presence of oxalic acid and calcium sulfate gave acetonide 18 (75%). Formylation of 18 afforded keto aldehyde 19 which was converted into 21 in three steps using Spencer's 11 methodology. Treatment of 19 with p-TsC1 in pyridine followed by addition of n-BuSH 12 yielded thioether 20.13 Reaction of 20 with dimethylsulfonium methylide afforded an intermediate oxathioacetal which after treatment with HgSO4 gave the furanoditerpene 21 (mp 202-203 oC) in 57% overall yield from 18.
2928
Scheme m
H ~
a''~ ff~O
OH 11
b'c
OH ~ :
OH
18: R = H 17
19: R = C H O
H e,
HO
f
O SBu-n O
OH
21
H
20
"O~.CH2C12.MeOH,-78°C;thenMe2S,n; bacetone, oxalic acid,CaSO, hrt,30hr; EtOCHO,MeOH(cat.), 0 °C, 3 hr, Et20, rt,7 hr.then cold aq. HCI, pH = 7;
c5 eq. Nail,
dp-TsCl,py, 0 °C, 1.5 hr; then n-BuSH,60 hr, 0 °C; eM¢:2S---CH2,DMSO. TI-IF, -5 °C (15rain) -> rt (30 rain); fagS04, Et20, rt. Acknowledgement: We are indebted to the donors of The Petroleum Research Fund, administered by
the American Chemical Society, for partial support of this research and one of us(M.W.) would like to thank the Burroughs Wellcome Foundation for a research fellowship. References and Notes
1. 2. 3. 4.
5. 6. 7. 8. 9. 10. 11. 12. 13.
For a recent review see: Faulkner, D. J. Nat. Prod. Rep. 1993, 497. Kohrnoto, S.; McConnell, O. J.; Wright, A.; Cross, S. Chemistry Letters 1987, 1687. Kazlauskas, R.; Murphy, P. T.; Wells, R. J.; Noack, K.; Oberhansli, W. E.; Schonholzer, P. Au.~'t. J. Chem. 1979, 32, 867. Tischler, M.; Anderson, R. J.; Choudhary, M. I.; Clardy, J. J. Org. Chem. 1991, 56, 42; Gustafson, K.; Anderson, R. J.; He, C.-H.; Clardy, J. TetrahedronLett. 1985, 26, 2521; Mayol, L.; Piccialli, V.; Sica, D. Gaze. Chim. Ital. 1988, 118,559. Baba, Y.; Sakamoto, T.; Kanematsu, K. Tetrahedron Lett. 1994, 35, 5677. Zoretic, P. A.; Weng X.; Caspar, M. L.; Davis, D. G. Tetrahedron Lett. 1991, 32, 4819. Johnson, W. S.; Lyle, T. A.; Daub, S. W. J. Org. Chem. 1982, 47, 163. Huckin, S. N.; Weiler, L. J. J. Am. Chem. Soc. 1974, 96, 1082. The complete details and spectra of the 2D NMR experiments will be published elsewhere. Hagiwara, H.; Uda, H.; Kodama~ T. J. Chem. Soc., Perkin Trans. 1 1980, 963. Garst, M. E.; Spencer, T. A. J. Am. Chem. Soc. 1973, 95, 252. Ireland, R. E.; Marshall, J. A. J. Org. Chem. 1962, 27, 1615. All new compounds gave satisfactory spectral and analytical data.
(Received in USA 3 January 1995; revised 28 February 1995; accepted 3 March 1995)
Pergamon 0040-4039(95)00433-5
A Biomimetic-Like Radical Approach To Furanoditerpenes PhiHip A. Zoretic*, Zhongqi Shen and Ming Wang ~cnt of Chemistry East CarolinaUniversity Greenville,NC 27858
Anthony A. Ribeiro DukeNMR SpectroscopyCenter Departmentof Radiology DukeUniversityMedicalCent~ Durham,NC 27710
Abstract: A highlystereoselectivcoxidativefree-radicalcyclizationofpolyone9 has beendemonstratedas a one step entryto a complextricaflx~yclicsTnthon10 whichcontainsfivecrucialstemogeniccenters. An entry the spongianand marginatanefuranoditerpeneshas beenrealizedfromsynthon10.
to
A variety of marine natural products I have been isolated from sponges which possess diverse biological activity. In particular the furanoditerpenes, spongiadiol 1, epispongiadiol 2, and isospongiadiol 3, isolated2 fi'om a deep water Caribbean sponge, Spongia sp. Linnaeus, exhibit activity against Herpessimplex virus, type 1 and P388 murine leukemia cells. The spongians 1 and 2 have also been isolated previously from Spongia species 3 collected in the Australian waters. The metabolites,4 marginafuran 4 and marginatone 5, possessing the rare marginatane carbon skeleton, have also been reported.
R1 R2
0.~"~~ OH 1: RI=H,R 2=OH
2: RI=OH,R 2=H
0 HOs.~~
0
OH 3
4:R= CO2H,R 1 =R2=H 5:Rffi CHa,R I = R 2 = O
Recently Kanematsu5 reported a tandem allene Diels-Alder bis-annulationapproach to the spongian skeleton. Herein we would like to communicate an alternative stereoselective biomimetic-
2925
2926
like radical cyclization strategy as a facile entry to the aforementioned natural products. It was anticipated, based on our previous work,6 that oxidative free-radical cyclization of 13-keto ester 9 would introduce stereoselectively five key chiral centers and also generate the necessary C-4 pro-13-hydroxymethylene in synthon 10. The C-14 exocyclic methylene would also provide an entry to both the spongian and marginatane furan ring systems. The synthesis of the targeted 13-ketoester 9 and the construction of the furan ring systems depicted in the spongians and marginatanes are delineated below. Reaction of allyl alcohol 66 with thionyl chloride7(Scheme I) and subsequent chromatography afforded an 87:13 ratio of rearranged allyl chloride 7 and allyl chloride 8. Alkylation of this mixture with the dianion 8 of ethyl 2-methylacetoacetate (generated from one equivalent of Nail followed by one equivalent of n-BuLi) gave I~-keto ester 9, after chromatography. Oxidative free-radical cyclization of 9, as a 0.1M solution in deaerated acetic acid, with a 2:1 molar ratio of Mn(OAc)y2H20 and Cu(OAc)2.H20 at 25 oc for one day under Ar yielded tricyclic keto ester I0 (mp 90-91 oc) in 43% yield. Scheme I
o•
(74%)
H
6
7
8 (66%)~b
1~'43%)
Et02C 10
0
C02Et 9
aSOCL2,CC14,rt; bLiCH2C(O)CMe(Na)CO2Et,THF, HMPA,0 °C, 2.5 hr; then aq. HCI; e2eq. Mn(OAc)3-2H20,1 eq. Cu(OAc)2.H20,de.aeratedHOAc,At, rt, 24 hr. In order to prove the stereochemistry depicted in 10 by NOE studies, a series of HMQC, HMBC and Cosy 2D NMR studies 9 were used to determine the assignment of each proton resonance signal in 10. Utilizing these assignments it was noted that irradiation of the C-10 angular methyl at 1.028 showed an enhancement of the C-2 axial proton (2.948), C-6 axial proton (2.118), C-11axial proton (1.488) and one methyleneoxy proton of the ester at 4.518. Likewise irradiation of the C-8 angular methyl showed an enhancement of the C-13 axial proton (2.308), C-11 axial proton (1.488), C-6 axial proton (2.118) and the C-7 equatorial proton (1.798), thus confirming the relative stereochemistry in 10.
2927
With the stereochemistryin I0 secured,our attentionwas turnedto the constructionof the marginatane and spongian furan ring systems as detailedbelow. Reduction of 10 (Scheme II)with L A H and subsequent dibenzoylationof dio111 (nap 165-166 oc) with benzoyl chlorideand 4 - D M A P in the presence of Et3N gave 12 (mp 193-194 oc). Ozonolysis of 12 and reductionof the resulting Scheme II
O
(94%,73%) RO
EtO2C
(52%) RzO OR 11: R = H
10
12: R = BZ
OBz 13
(88%= d)~ OH
RO
-(82%, OR 15: R = Bz 16: R = H
78%)BzOV ~H v OBz 14
=[.A_l-I,Et20, reflux; ~COC1, 4-DMAP,Et3N,CH2C12,rt, 2 hr; eO3,CH2C12,-78 0C; then Ph3P; dl.5 eq. LDA, THF, -78 °C; then 2.3 eq. of ZnCI2,followedby 2.0 eq. of CHOCH2OT/-IP, -78 °C -> -45 °(2 -> 0 °C ; sat. Nil 4C1; eaq.THF,p-TsOH,62 °(2 - 70 °(2,50 min. ozonide with Ph3P afforded ketone 13 (mp 211-211.5 oC), after chromatography. A direct route to the marginatane furan ring system was realized by modification of Hagiwara's l0 procedure. Thus reaction of the lithium enolate of 13 (generated from LDA at -78 °C) with 2.3 equivalents of ZnC12 followed by aldol condensation of the resulting zinc enolate with 2.0 equivalents of CHOCH2OTHP (-78 oC -> -45 oC -> 0 °C) yielded the 13-hydroxyketones 14, after chromatography. Concomitant hydrolysis of 14 with aqueous THF in the presence ofp-TsOH gave IS (mp 138-138.5 oc) and subsequent hydride reduction of I5 with LAH afforded diol 16 (mp 216-217 oc). A direct route to the 3, 4-disubstituted furan ring system in the spongians was realized as outlined in Scheme HI. Ozonolysis of diol 11 and subsequent reaction of ketone 17 (mp 166-166.5 oC) with acetone in the presence of oxalic acid and calcium sulfate gave acetonide 18 (75%). Formylation of 18 afforded keto aldehyde 19 which was converted into 21 in three steps using Spencer's 11 methodology. Treatment of 19 with p-TsC1 in pyridine followed by addition of n-BuSH 12 yielded thioether 20.13 Reaction of 20 with dimethylsulfonium methylide afforded an intermediate oxathioacetal which after treatment with HgSO4 gave the furanoditerpene 21 (mp 202-203 oC) in 57% overall yield from 18.
2928
Scheme m
H ~
a''~ ff~O
OH 11
b'c
OH ~ :
OH
18: R = H 17
19: R = C H O
H e,
HO
f
O SBu-n O
OH
21
H
20
"O~.CH2C12.MeOH,-78°C;thenMe2S,n; bacetone, oxalic acid,CaSO, hrt,30hr; EtOCHO,MeOH(cat.), 0 °C, 3 hr, Et20, rt,7 hr.then cold aq. HCI, pH = 7;
c5 eq. Nail,
dp-TsCl,py, 0 °C, 1.5 hr; then n-BuSH,60 hr, 0 °C; eM¢:2S---CH2,DMSO. TI-IF, -5 °C (15rain) -> rt (30 rain); fagS04, Et20, rt. Acknowledgement: We are indebted to the donors of The Petroleum Research Fund, administered by
the American Chemical Society, for partial support of this research and one of us(M.W.) would like to thank the Burroughs Wellcome Foundation for a research fellowship. References and Notes
1. 2. 3. 4.
5. 6. 7. 8. 9. 10. 11. 12. 13.
For a recent review see: Faulkner, D. J. Nat. Prod. Rep. 1993, 497. Kohrnoto, S.; McConnell, O. J.; Wright, A.; Cross, S. Chemistry Letters 1987, 1687. Kazlauskas, R.; Murphy, P. T.; Wells, R. J.; Noack, K.; Oberhansli, W. E.; Schonholzer, P. Au.~'t. J. Chem. 1979, 32, 867. Tischler, M.; Anderson, R. J.; Choudhary, M. I.; Clardy, J. J. Org. Chem. 1991, 56, 42; Gustafson, K.; Anderson, R. J.; He, C.-H.; Clardy, J. TetrahedronLett. 1985, 26, 2521; Mayol, L.; Piccialli, V.; Sica, D. Gaze. Chim. Ital. 1988, 118,559. Baba, Y.; Sakamoto, T.; Kanematsu, K. Tetrahedron Lett. 1994, 35, 5677. Zoretic, P. A.; Weng X.; Caspar, M. L.; Davis, D. G. Tetrahedron Lett. 1991, 32, 4819. Johnson, W. S.; Lyle, T. A.; Daub, S. W. J. Org. Chem. 1982, 47, 163. Huckin, S. N.; Weiler, L. J. J. Am. Chem. Soc. 1974, 96, 1082. The complete details and spectra of the 2D NMR experiments will be published elsewhere. Hagiwara, H.; Uda, H.; Kodama~ T. J. Chem. Soc., Perkin Trans. 1 1980, 963. Garst, M. E.; Spencer, T. A. J. Am. Chem. Soc. 1973, 95, 252. Ireland, R. E.; Marshall, J. A. J. Org. Chem. 1962, 27, 1615. All new compounds gave satisfactory spectral and analytical data.
(Received in USA 3 January 1995; revised 28 February 1995; accepted 3 March 1995)