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Synthesis of key intermediates for a concise and convergent approach to the marine natural product eleutherobin
TETRAHEDRON LETTERS Tetrahedron Letters 40 (1999) 9321-9324
Pergamon
Synthesis of key intermediates for a concise and convergent approach to the marine natural product eleutherobin Anne Baron, Vittorio Caprio and John Mann*
Chemistry Department, Reading University, Whiteknights, Reading RG6 6AD, UK Received 29 September 1999; accepted 13 October 1999
Abstract Synthesis of 1,6-syn-5,6-anti-2-methyl-5-isopropyl-bicyclo[4.3.0]-non-2-en-8-one in three steps from (rac)-phellandrene; and 1,6-syn-l-methyl-6-methoxy-3-aza-9-oxabicyclo[4.2.1]non-7-en-4-one in five steps from 2-methoxy-5-methylfuran and tetrabromoacetone, provided these key intermediates for the construction of the skeleton of eleutherobin. © 1999 Elsevier Science Ltd. All rights reserved.
The chemical structure of eleutherobin, from a marine soft coral Eleutherobia albiflora, was first reported in 1997 by the group of Fenical, I though its cytotoxicity had been revealed in a patent two years earlier. It was shown to possess potent activity against a range of human breast, renal, ovarian, and lung cancer cell lines with a mean cytotoxicity that was at least 100 times greater than that exhibited by taxol or the recently described epothilones. 2 Like these compounds it stabilises microtubules against depolymerisation.
O Me
Me"
"Me
O._/~Me~
Me ["
d
~co
eleutherobin ~ O ~
OH OH
Eleutherobin has already been the target of two total syntheses, 3'4 but both of these routes were essentially linear and were elegant rather than practical. Our proposed route (analysis shown in Scheme I) is both concise and convergent, and should allow access to not only the skeleton of eleutherobin but also to a range of analogues for biological evaluation.
*Corresponding author. John Mann and Anne Baron are now in the School of Chemistry, Queen's University Belfast, Belfast BT9 5AG (email: [email protected])
0040-4039/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(99)01956-5
9322
Me
Me H
OR~.
O II Me
e ~ CH2
H
---> kl?l Me"
_.~)
OMe
I-
"N
00Me
-Me R'O
U Me
lvl
Me
Me
o
o OMe
M
M
C
D Scheme 1
The key intermediate D was prepared from rac-phellandrene 1 via regio-selective addition of dichloroketene5 to provide dichlorocyclobutanone 2, followed by ring expansion with diazomethane6 and dechlorination of the resultant dichlorocyclopentanone 3 using zinc in acetic acid. The overall yield for this three step process (Scheme 2) was around 37%. 7 Me
Me CI3CCOCI, Zn, Et20
C1
ultrasound, 15°C to R~
~
80%
M
CH2N2 ~
e
0°CtoRT
M
1
2
Zn, AcOH
Me S
3
4~7%47%over 2 steps
D
Scheme 2
Intermediate C was prepared via the sequence shown in Scheme 3. The crucial reaction was the cycloaddition of the oxyallyl from tetrabromoacetone with 2-methoxy-5-methylfuran 4. The use of EtzZn for this reaction is a recent innovation8 that has been adopted (with
9323
excellent results) by other groups. 9 The oxabicycle 6 was obtained in 37% yield (for the two steps) on the multigram scale, s° At this stage a Baeyer-Villiger reaction was considered, but although we II and others 12 have demonstrated the viability of such Baeyer-Villiger reactions, we were concerned about the stability of the alkene. In consequence, we investigated the feasibility of effecting a regioselective Beckmann rearrangement. In fact, the two possible oxime mesylates 7 were formed in equal amounts, but could be readily separated by flash chromatography, thus allowing access to the desired regioisomeric amide (intermediate C) after the Beckmann rearrangement] 3 The structure of this compound was proved by X-ray structural analysis.
HH~
l-BuLl, Et20, reflux 2-12'°°c to RT ~-~ ill Me 3-NaOMe,CuBr,RT MeO 58%
TBA, Et2ZnID Me 0°C,toluene
r
Br7
4 5
NH4CI, ZrdCu MeOH, RT 1 37% over2 steps O 0 - ~ - Me Me
O
OMe q 1-NH2OH.HCI,NaHCO3,MeOH.reflux M e ~ 2-MsC1,plcridine,DCM,0°C to RT 42% of
7 THF,buffersolution reflux
H
M e ~
OMe
required m e s y l a t e 7
92%
O
OMe C Scheme 3
With these two intermediates available in multigram amounts we are exploring routes for their conversion into the basic skeleton of eleutherobin, as envisaged in Scheme 1. While both compounds are racemic, fragment D could be prepared from the very expensive (-)phellandrene or by resolution of its diastereoisomeric oxazolidines formed with (+) or (-)ephedrines.t4 Resolution of the oxazolidines formed from ketone 6 should also provide access to homochiral intermediate C.
Acknowledgements Anne Baron thanks the Royal Society of Chemistry (Adrien Albert Bequest) for financial support.
9324
References (1) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.; Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744. (2) Hofle, G.; Bedorf, N.; Steinmetz, H.; Schomberg, D.; Gerth, K.; Reichenbach, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1567. (3) Nicolaou, K. C.; van Delft, F.; Oshima, T.; Vourloumis, D.; Xu, J.; Hoskawa, S.; Pfefferkorn, J.; Kim, S.; Li, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2520. (4) Chen, X-T.; Gutterideg, C. E.; Bhattacharya, S. K.; Zhou, B.; Pettus, T. R. R.; Hascall, R.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 185 and 789. (5) Parker, M. S.; Rizzo, C. J. Synth. Commun. 1995, 25, 2781. (6) Greene, A. E.; Depr6s, J-P. J. Am. Chem. Soc. 1979, 101, 4003. (7) A solution of phellandrene (4g, 14.68mmol) and zinc dust (1.92g, 29.36mmol) in dried diethyl ether (50ml) was sonicated for 15min. before adding dropwise over 45min. a solution of trichloroacetylchloride (2.46ml, 22.02mmol) in dried diethyl ether (25ml). The temperature was monitored at 15°C and the reaction mixture sonicated for 3h30 including addition time. Diethyl ether (30ml) was added and the zinc dust was filtered. The filtrate was washed with water (100ml), an aqueous saturated solution of NaCI (100ml) and dried over magnesium sulphate. The crude compound was then purified by column chromatography on silica gel (petroleum ether/diethyl ether:95/5) to give 2.95g of 2 as a colourless oil (yield:80%). Diazomethane (3eq.) (freshly distilled) was poured into a solution of dichloroketone 2 (lg, 4.05mmol) in diethyl ether (15ml) at 0°C. The reaction mixture was allowed to warm to room temperature and then quenched with few drops of acetic acid. The crude product 3 was then dechlorinated 15 and purified to afford compound D as a yellow oil (yield:47%). (8) de Almeida Barbosa, L-C.; Mann, J. Synthesis 1996, 31. (9) See for example: Lautens, M.; Aspiotis, R.; Colucci, J. J. Amer. Chem. Soc. 1996, 118, 10930.; Turner, D.; Vogel, P. Synlett. 1998, 304. (10) Diethyl zinc (1.1M in toluene)(62.2ml, 68.40mmol) was added dropwise to a solution of 2-methoxy-5-methylfuran (5.90g, 52.62mmol) and tetrabromoacetone (25.56g, 68.40mmol) in toluene (380ml) at 0°C under argon. The reaction mixture was stirred at 0°C for lh and at room temperature for 18 hours. The reaction was quenched by adding saturated aqueous solution of NHnC1 (120ml) and ethyl acetate (120ml). After filtration the 2 layers were separated. The organic layer was washed with NHaC1 (120ml). The combined aqueous phases were further extracted with ethyl acetate (2x120ml) and the organic extracts were dried over magnesium sulfate. Solvent was removed under reduced pressure and the resulting brown oil used for the next step without further purification. The crude dibromoadduct 5 was dissolved in saturated methanolic ammonium chloride (250ml) and Zn/Cu couple (26.5g) added portionwise at room temperature. The reaction mixture was stirred 5h at room temperature. After filtration of Zn/Cu couple, ethyl acetate (120ml) and an aqueous saturated solution of NaCI (100ml) were added to the filtrate. After filtration the 2 layers were separated. The aqueous phase was further extracted with ethyl acetate (4×120ml) and the combined organic extracts dried over magnesium sulphate. Solvent was removed under reduced pressure to give 22g of crude product. 6 was then purified by column chromatography on silica gel (petroleum ether/ethyl acetate: 9/1) to yield 3.3g of pure ketone as an orange oil (yield:37%). (11) Mann, J. Tetrahedron 1986, 42, 4611. (12) Noyori, R.; Sato, T.; Kobayashi, H. Tetrahedron Lett. 1980, 21, 2569 and 2573. (13) Veronique Morisson thesis, 1997, Orsay university (Paris XI, France). (14) See for example: Kelly, R.; Van Rheenan, V. Tetrahedron Lett. 1973, 14, 1709. (15) Jeffs, P. W.; Molina, G.; Cass, M. W.; Cortese, N. A. J. Org. Chem. 1982, 47, 3871.
Pergamon
Synthesis of key intermediates for a concise and convergent approach to the marine natural product eleutherobin Anne Baron, Vittorio Caprio and John Mann*
Chemistry Department, Reading University, Whiteknights, Reading RG6 6AD, UK Received 29 September 1999; accepted 13 October 1999
Abstract Synthesis of 1,6-syn-5,6-anti-2-methyl-5-isopropyl-bicyclo[4.3.0]-non-2-en-8-one in three steps from (rac)-phellandrene; and 1,6-syn-l-methyl-6-methoxy-3-aza-9-oxabicyclo[4.2.1]non-7-en-4-one in five steps from 2-methoxy-5-methylfuran and tetrabromoacetone, provided these key intermediates for the construction of the skeleton of eleutherobin. © 1999 Elsevier Science Ltd. All rights reserved.
The chemical structure of eleutherobin, from a marine soft coral Eleutherobia albiflora, was first reported in 1997 by the group of Fenical, I though its cytotoxicity had been revealed in a patent two years earlier. It was shown to possess potent activity against a range of human breast, renal, ovarian, and lung cancer cell lines with a mean cytotoxicity that was at least 100 times greater than that exhibited by taxol or the recently described epothilones. 2 Like these compounds it stabilises microtubules against depolymerisation.
O Me
Me"
"Me
O._/~Me~
Me ["
d
~co
eleutherobin ~ O ~
OH OH
Eleutherobin has already been the target of two total syntheses, 3'4 but both of these routes were essentially linear and were elegant rather than practical. Our proposed route (analysis shown in Scheme I) is both concise and convergent, and should allow access to not only the skeleton of eleutherobin but also to a range of analogues for biological evaluation.
*Corresponding author. John Mann and Anne Baron are now in the School of Chemistry, Queen's University Belfast, Belfast BT9 5AG (email: [email protected])
0040-4039/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII: S0040-4039(99)01956-5
9322
Me
Me H
OR~.
O II Me
e ~ CH2
H
---> kl?l Me"
_.~)
OMe
I-
"N
00Me
-Me R'O
U Me
lvl
Me
Me
o
o OMe
M
M
C
D Scheme 1
The key intermediate D was prepared from rac-phellandrene 1 via regio-selective addition of dichloroketene5 to provide dichlorocyclobutanone 2, followed by ring expansion with diazomethane6 and dechlorination of the resultant dichlorocyclopentanone 3 using zinc in acetic acid. The overall yield for this three step process (Scheme 2) was around 37%. 7 Me
Me CI3CCOCI, Zn, Et20
C1
ultrasound, 15°C to R~
~
80%
M
CH2N2 ~
e
0°CtoRT
M
1
2
Zn, AcOH
Me S
3
4~7%47%over 2 steps
D
Scheme 2
Intermediate C was prepared via the sequence shown in Scheme 3. The crucial reaction was the cycloaddition of the oxyallyl from tetrabromoacetone with 2-methoxy-5-methylfuran 4. The use of EtzZn for this reaction is a recent innovation8 that has been adopted (with
9323
excellent results) by other groups. 9 The oxabicycle 6 was obtained in 37% yield (for the two steps) on the multigram scale, s° At this stage a Baeyer-Villiger reaction was considered, but although we II and others 12 have demonstrated the viability of such Baeyer-Villiger reactions, we were concerned about the stability of the alkene. In consequence, we investigated the feasibility of effecting a regioselective Beckmann rearrangement. In fact, the two possible oxime mesylates 7 were formed in equal amounts, but could be readily separated by flash chromatography, thus allowing access to the desired regioisomeric amide (intermediate C) after the Beckmann rearrangement] 3 The structure of this compound was proved by X-ray structural analysis.
HH~
l-BuLl, Et20, reflux 2-12'°°c to RT ~-~ ill Me 3-NaOMe,CuBr,RT MeO 58%
TBA, Et2ZnID Me 0°C,toluene
r
Br7
4 5
NH4CI, ZrdCu MeOH, RT 1 37% over2 steps O 0 - ~ - Me Me
O
OMe q 1-NH2OH.HCI,NaHCO3,MeOH.reflux M e ~ 2-MsC1,plcridine,DCM,0°C to RT 42% of
7 THF,buffersolution reflux
H
M e ~
OMe
required m e s y l a t e 7
92%
O
OMe C Scheme 3
With these two intermediates available in multigram amounts we are exploring routes for their conversion into the basic skeleton of eleutherobin, as envisaged in Scheme 1. While both compounds are racemic, fragment D could be prepared from the very expensive (-)phellandrene or by resolution of its diastereoisomeric oxazolidines formed with (+) or (-)ephedrines.t4 Resolution of the oxazolidines formed from ketone 6 should also provide access to homochiral intermediate C.
Acknowledgements Anne Baron thanks the Royal Society of Chemistry (Adrien Albert Bequest) for financial support.
9324
References (1) Lindel, T.; Jensen, P. R.; Fenical, W.; Long, B. H.; Casazza, A. M.; Carboni, J.; Fairchild, C. R. J. Am. Chem. Soc. 1997, 119, 8744. (2) Hofle, G.; Bedorf, N.; Steinmetz, H.; Schomberg, D.; Gerth, K.; Reichenbach, H. Angew. Chem., Int. Ed. Engl. 1996, 35, 1567. (3) Nicolaou, K. C.; van Delft, F.; Oshima, T.; Vourloumis, D.; Xu, J.; Hoskawa, S.; Pfefferkorn, J.; Kim, S.; Li, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2520. (4) Chen, X-T.; Gutterideg, C. E.; Bhattacharya, S. K.; Zhou, B.; Pettus, T. R. R.; Hascall, R.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1998, 37, 185 and 789. (5) Parker, M. S.; Rizzo, C. J. Synth. Commun. 1995, 25, 2781. (6) Greene, A. E.; Depr6s, J-P. J. Am. Chem. Soc. 1979, 101, 4003. (7) A solution of phellandrene (4g, 14.68mmol) and zinc dust (1.92g, 29.36mmol) in dried diethyl ether (50ml) was sonicated for 15min. before adding dropwise over 45min. a solution of trichloroacetylchloride (2.46ml, 22.02mmol) in dried diethyl ether (25ml). The temperature was monitored at 15°C and the reaction mixture sonicated for 3h30 including addition time. Diethyl ether (30ml) was added and the zinc dust was filtered. The filtrate was washed with water (100ml), an aqueous saturated solution of NaCI (100ml) and dried over magnesium sulphate. The crude compound was then purified by column chromatography on silica gel (petroleum ether/diethyl ether:95/5) to give 2.95g of 2 as a colourless oil (yield:80%). Diazomethane (3eq.) (freshly distilled) was poured into a solution of dichloroketone 2 (lg, 4.05mmol) in diethyl ether (15ml) at 0°C. The reaction mixture was allowed to warm to room temperature and then quenched with few drops of acetic acid. The crude product 3 was then dechlorinated 15 and purified to afford compound D as a yellow oil (yield:47%). (8) de Almeida Barbosa, L-C.; Mann, J. Synthesis 1996, 31. (9) See for example: Lautens, M.; Aspiotis, R.; Colucci, J. J. Amer. Chem. Soc. 1996, 118, 10930.; Turner, D.; Vogel, P. Synlett. 1998, 304. (10) Diethyl zinc (1.1M in toluene)(62.2ml, 68.40mmol) was added dropwise to a solution of 2-methoxy-5-methylfuran (5.90g, 52.62mmol) and tetrabromoacetone (25.56g, 68.40mmol) in toluene (380ml) at 0°C under argon. The reaction mixture was stirred at 0°C for lh and at room temperature for 18 hours. The reaction was quenched by adding saturated aqueous solution of NHnC1 (120ml) and ethyl acetate (120ml). After filtration the 2 layers were separated. The organic layer was washed with NHaC1 (120ml). The combined aqueous phases were further extracted with ethyl acetate (2x120ml) and the organic extracts were dried over magnesium sulfate. Solvent was removed under reduced pressure and the resulting brown oil used for the next step without further purification. The crude dibromoadduct 5 was dissolved in saturated methanolic ammonium chloride (250ml) and Zn/Cu couple (26.5g) added portionwise at room temperature. The reaction mixture was stirred 5h at room temperature. After filtration of Zn/Cu couple, ethyl acetate (120ml) and an aqueous saturated solution of NaCI (100ml) were added to the filtrate. After filtration the 2 layers were separated. The aqueous phase was further extracted with ethyl acetate (4×120ml) and the combined organic extracts dried over magnesium sulphate. Solvent was removed under reduced pressure to give 22g of crude product. 6 was then purified by column chromatography on silica gel (petroleum ether/ethyl acetate: 9/1) to yield 3.3g of pure ketone as an orange oil (yield:37%). (11) Mann, J. Tetrahedron 1986, 42, 4611. (12) Noyori, R.; Sato, T.; Kobayashi, H. Tetrahedron Lett. 1980, 21, 2569 and 2573. (13) Veronique Morisson thesis, 1997, Orsay university (Paris XI, France). (14) See for example: Kelly, R.; Van Rheenan, V. Tetrahedron Lett. 1973, 14, 1709. (15) Jeffs, P. W.; Molina, G.; Cass, M. W.; Cortese, N. A. J. Org. Chem. 1982, 47, 3871.