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Stereoselective synthesis of the right-hand segment of tubiferal A
Tetrahedron Letters 55 (2014) 1145–1147
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of the right-hand segment of tubiferal A Takahiro Hiramatsu a, Motomasa Takahashi b, Keiji Tanino b,⇑ a b
Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0810, Japan Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
a r t i c l e
i n f o
Article history: Received 4 November 2013 Revised 6 December 2013 Accepted 18 December 2013 Available online 27 December 2013 Keywords: Tubiferal A Total synthesis Semi pinacol rearrangement Hydrindane skeleton
a b s t r a c t Tubiferal A, a triterpenoid isolated from myxomycete Tubifera dimorphotheca, exhibits a reversal effect of vincristine (VCR) resistance against VCR-resistant KB cell lines. The compound possesses a complex structure involving the 6-7-6-5 polycyclic carbon framework with various functional groups. The stereoselective synthesis of the right-hand segment of tubiferal A was achieved on the basis of the cyclopentene annulation method and the semi-pinacol rearrangement reaction of an epoxy alcohol for constructing the trans-fused 6-5 bicyclic skeleton possessing two quaternary carbon atoms at the angular positions. Ó 2013 Elsevier Ltd. All rights reserved.
Tubiferal A (1) was isolated from field-collected fruit bodies of the myxomycete Tubifera dimorphotheca by Ishibashi and co-workers in 2004.1 The compound exhibits a reversal effect of vincristine (VCR) resistance against VCR-resistant KB cell lines (IC50 Value: 2.7 lg/mL). The remarkable biological properties as well as the complex structure involving the 6-7-6-5 polycyclic carbon framework with various functional groups prompted us to undertake the synthetic studies of 1. Since the construction of the trans-fused CD ring system of 1 possessing two quaternary carbon atoms at the angular positions was expected to be difficult, we planned to synthesize the right-hand segment involving the CDE ring system on the basis of the strategy developed for the total synthesis of solanoeclepin A (2) (Fig. 1). In 2011, we reported the first asymmetric total synthesis of solanoeclepin A,2 a hatch-stimulating substance of the potato cyst nematode. The natural compound possesses a complex heptacyclic core skeleton involving a trans-hydrindane substructure with two quaternary stereogenic carbon atoms at the angular positions. While the stereoselective construction of the strained bicyclic system was difficult, we developed a strategy on the basis of the semi-pinacol rearrangement reaction of an epoxy alcohol3 as shown in Scheme 1. Bicyclic allyl ester 3, which was readily obtained in optically active form from commercially available enone in five steps,4 was transformed into enone 6 through the m-chloroperbenzoic acid (mCPBA) oxidation affording epoxide 4, the Meinwald rearrangement of epoxide 4 mediated by methylaluminum bis(trifluoromethanesulfonate), and treatment of the resulting ketone 5 with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction of enone 6 with the organocerium reagent prepared from vinylmagnesium bromide gave alcohol 7 through introduction of the vinyl group from the opposite face of the angular methyl group and the cyano group. In the presence of Ti(OiPr)4, 7 was oxidized with tert-butyl hydroperoxide (TBHP) in chemo- and stereoselective manner to afford a-epoxy alcohol 8. Finally, the 1,2-rearrangement of the vinyl group effected by trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine gave the desired ketone 9 having the trans-hydrindane skeleton in almost quantitative yield. These results led us to design tricyclic compound 10 as a key intermediate of the asymmetric total synthesis of tubiferal A (Scheme 2). The vinyl group of 10 would serve as a useful precursor of a formyl group, and the c-lactone moiety would be constructed from bicyclic compound 11 through transformation of the cyano group followed by 1,2-transposition of the cyclopentanone moiety.
⇑ Corresponding author. E-mail address: [email protected] (K. Tanino). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.12.069
Figure 1. Structures of tubiferal A and solanoeclepin A.
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T. Hiramatsu et al. / Tetrahedron Letters 55 (2014) 1145–1147
Scheme 1. Construction of the trans-hydrindane skeleton.2
Scheme 3. Synthesis of ketone 18 with trans-hydrindane skeleton.
Scheme 2. Synthetic strategy of tubiferal A.
The synthesis of 10 was started with acetate 12, the corresponding enantiomer of 3 in Scheme 1, through a similar threestep conversion to enone 13 (Scheme 3). After the stereoselective 1,2-addition reaction with the vinylcerium reagent providing alcohol 14, elongation of the side chain with b-configuration was conducted prior to the semi-pinacol rearrangement reaction. Thus, reduction of the cyano group with diisobutylaluminum hydride (DIBAH) afforded the corresponding aldehyde that in turn was reacted with (methoxymethylene) triphenylphosphorane to give enol ether 15. Stereoselective oxidation to epoxide 16 followed by the semi-pinacol rearrangement promoted by TMSOTf and 2,6-lutidine led to the formation of ketone 17 without affecting the enol ether moiety. Treatment of 17 with pyridinium p-toluenesulfonate (PPTS) in MeOH effected formation of the acetal moiety and removal of the TMS group, and the resulting alcohol was protected with a methoxymethyl (MOM) group to yield 18. Having the desired trans-hydrindane derivative with two quaternary asymmetric carbon atoms at the angular positions in hand, the stage was set for the stereoselective construction of the c-lactone moiety (Scheme 4). With a view to achieving 1,2-transposition of the cyclopentanone moiety, ketone 18 was converted to ketol 20 through the Rubottom reaction5 of enol silyl ether 19. On refluxing in toluene with Al(OiPr)3,6 ketol 20 afforded a mixture of 20 and its isomer 21 which was easily separated by silica gel chromatography. The hydroxyl group of 21 was then removed by reduction of the corresponding acetate with SmI2.7 Finally, ketone 22 was transformed into the right-hand segment of tubiferal A as shown in Scheme 5. Keto acid 23, which was obtained through hydrolysis of acetal 22 followed by the Pinnick
Scheme 4. 1,2-Transposition of the cyclopentanone moiety.
Scheme 5. Synthesis of lactone 10, the right-hand segment of tubiferal A.
T. Hiramatsu et al. / Tetrahedron Letters 55 (2014) 1145–1147
oxidation,8 was reduced with NaBH4 in the presence of CeCl3 in MeOH to afford a 4:1 mixture of epimers. The hydride attack occurred mainly from the opposite face of the acetic acid side chain, and c-lactone 25 was obtained after acidic workup. It is noteworthy that the minor epimer 24, which failed to form the corresponding c-lactone under acidic conditions, was removed simply by treating with an aqueous NaHCO3 solution. The homoprenyl chain was then introduced by successive treatment of lactone 25 with lithium diisopropylamide (LDA), hexamethylphosphoric triamide (HMPA), and 5-iodo-2-methyl-2pentene. Although the reaction afforded the undesired epimer 26 through alkylation from the convex face of the lactone moiety, regeneration of the enolate9 followed by protonation with methyl salicylate10,11 led to formation of the desired isomer 10.12 In conclusion, we have achieved the asymmetric synthesis of the right-hand segment of tubiferal A. The semi-pinacol rearrangement of an epoxy alcohol was employed for the construction of the trans-hydrindane skeleton with two quaternary stereogenic carbon atoms at the angular positions. We are currently exploring the method for the stereoselective construction of the left-hand moiety of tubiferal A. Acknowledgments This work was partially supported by the Global COE Program (Project No. B01: Catalysis as the Basis for Innovation in Materials Science) and Grant-in-Aid for Scientific Research on Innovative Areas (Project No. 2105: Organic Synthesis Based on Reaction Integration) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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References and notes 1. Kamata, K.; Onuki, H.; Hirota, H.; Yamamoto, Y.; Hayashi, M.; Komiyama, K.; Sato, M.; Ishibashi, M. Tetrahedron 2004, 60, 9835–9839. 2. Tanino, K.; Takahashi, M.; Tomata, Y.; Tokura, H.; Uehara, T.; Narabu, T.; Miyashita, M. Nat. Chem. 2011, 3, 484–488. 3. (a) Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.; Shimazaki, M.; Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 3827–3829; (b) Suzuki, K.; Miyazawa, M.; Shimazaki, M.; Tsuchihashi, G. Tetrahedron Lett. 1986, 27, 6237– 6240. 4. Tanino, K.; Tomata, Y.; Shiina, Y.; Miyashita, M. Eur. J. Org. Chem. 2006, 328– 334. 5. Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1978, 43, 1599–1602. 6. Paquette, L. A.; Hofferberth, J. E. Org. React. 2003, 62, 477–567. 7. Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135–1138. 8. (a) Kuras, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825–4830; (b) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096. 9. We found that the enolate was gradually decomposed when the reaction was allowed to warm up from 78 °C to 50 °C. 10. Krause, N. Angew. Chem., Int. Ed. 1994, 33, 1764–1765. 11. The desired isomer 10 was formed as a sole product, while the chemical yield was not so high. On the other hand, the use of acetic acid instead of methyl salicylate gave a 4:1 mixture of 10 and 26. 12. Spectral data for 10: ½a26 D 12.28 (c 0.09, CH2Cl2); IR (neat) 3080, 2926, 2871, 2855, 1771, 1627, 1466, 1449, 1377, 1152, 1193, 1036, 970, 919, 846, 805 cm1. 1H NMR (500 MHz, CDCl3) d 6.26 (1H, dd, J = 17.0, 11.0 Hz), 5.14 (1H, d, J = 11.0 Hz), 5.12 (1H, d, J = 17.0 Hz), 5.09 (1H, t, J = 6.5 Hz), 4.68 (1H, ddd, J = 8.0, 7.5, 5.0 Hz), 4.63 (1H, d, J = 7.0 Hz), 4.54 (1H, d, J = 7.0 Hz), 3.54 (1H, t, J = 2.5 Hz), 3.37 (3H, s), 2.61 (1H, ddd, J = 8.0, 7.5, 5.0 Hz), 2.44 (1H, dd, J = 8.0, 7.5 Hz), 2.34 (1H, dd, J = 13.5, 7.0 Hz), 2.28 (1H, dd, J = 13.5, 5.0 Hz), 2.15 (1H, dd, J = 14.0, 7.5 Hz), 2.00 (1H, m), 1.87 (1H, m), 1.71–1.65 (5H, m, involving a singlet at 1.70), 1.64–1.49 (8H, m, involving a singlet at 1.62), 1.22 (3H, s); 13C NMR (125 MHz, CDCl3) d 179.43, 142.35, 133.03, 123.42, 115.31, 95.84, 81.61, 79.47, 55.56, 55.16, 50.17, 44.55, 42.89, 34.01, 31.53, 29.72, 27.17, 25.78, 25.20, 18.14, 17.85, 16.96.; HRMS (FD) calcd for C22H34O4 (M+): 362.24571, found 362.24677.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of the right-hand segment of tubiferal A Takahiro Hiramatsu a, Motomasa Takahashi b, Keiji Tanino b,⇑ a b
Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo 060-0810, Japan Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
a r t i c l e
i n f o
Article history: Received 4 November 2013 Revised 6 December 2013 Accepted 18 December 2013 Available online 27 December 2013 Keywords: Tubiferal A Total synthesis Semi pinacol rearrangement Hydrindane skeleton
a b s t r a c t Tubiferal A, a triterpenoid isolated from myxomycete Tubifera dimorphotheca, exhibits a reversal effect of vincristine (VCR) resistance against VCR-resistant KB cell lines. The compound possesses a complex structure involving the 6-7-6-5 polycyclic carbon framework with various functional groups. The stereoselective synthesis of the right-hand segment of tubiferal A was achieved on the basis of the cyclopentene annulation method and the semi-pinacol rearrangement reaction of an epoxy alcohol for constructing the trans-fused 6-5 bicyclic skeleton possessing two quaternary carbon atoms at the angular positions. Ó 2013 Elsevier Ltd. All rights reserved.
Tubiferal A (1) was isolated from field-collected fruit bodies of the myxomycete Tubifera dimorphotheca by Ishibashi and co-workers in 2004.1 The compound exhibits a reversal effect of vincristine (VCR) resistance against VCR-resistant KB cell lines (IC50 Value: 2.7 lg/mL). The remarkable biological properties as well as the complex structure involving the 6-7-6-5 polycyclic carbon framework with various functional groups prompted us to undertake the synthetic studies of 1. Since the construction of the trans-fused CD ring system of 1 possessing two quaternary carbon atoms at the angular positions was expected to be difficult, we planned to synthesize the right-hand segment involving the CDE ring system on the basis of the strategy developed for the total synthesis of solanoeclepin A (2) (Fig. 1). In 2011, we reported the first asymmetric total synthesis of solanoeclepin A,2 a hatch-stimulating substance of the potato cyst nematode. The natural compound possesses a complex heptacyclic core skeleton involving a trans-hydrindane substructure with two quaternary stereogenic carbon atoms at the angular positions. While the stereoselective construction of the strained bicyclic system was difficult, we developed a strategy on the basis of the semi-pinacol rearrangement reaction of an epoxy alcohol3 as shown in Scheme 1. Bicyclic allyl ester 3, which was readily obtained in optically active form from commercially available enone in five steps,4 was transformed into enone 6 through the m-chloroperbenzoic acid (mCPBA) oxidation affording epoxide 4, the Meinwald rearrangement of epoxide 4 mediated by methylaluminum bis(trifluoromethanesulfonate), and treatment of the resulting ketone 5 with
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction of enone 6 with the organocerium reagent prepared from vinylmagnesium bromide gave alcohol 7 through introduction of the vinyl group from the opposite face of the angular methyl group and the cyano group. In the presence of Ti(OiPr)4, 7 was oxidized with tert-butyl hydroperoxide (TBHP) in chemo- and stereoselective manner to afford a-epoxy alcohol 8. Finally, the 1,2-rearrangement of the vinyl group effected by trimethylsilyl trifluoromethanesulfonate (TMSOTf) and 2,6-lutidine gave the desired ketone 9 having the trans-hydrindane skeleton in almost quantitative yield. These results led us to design tricyclic compound 10 as a key intermediate of the asymmetric total synthesis of tubiferal A (Scheme 2). The vinyl group of 10 would serve as a useful precursor of a formyl group, and the c-lactone moiety would be constructed from bicyclic compound 11 through transformation of the cyano group followed by 1,2-transposition of the cyclopentanone moiety.
⇑ Corresponding author. E-mail address: [email protected] (K. Tanino). 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.12.069
Figure 1. Structures of tubiferal A and solanoeclepin A.
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T. Hiramatsu et al. / Tetrahedron Letters 55 (2014) 1145–1147
Scheme 1. Construction of the trans-hydrindane skeleton.2
Scheme 3. Synthesis of ketone 18 with trans-hydrindane skeleton.
Scheme 2. Synthetic strategy of tubiferal A.
The synthesis of 10 was started with acetate 12, the corresponding enantiomer of 3 in Scheme 1, through a similar threestep conversion to enone 13 (Scheme 3). After the stereoselective 1,2-addition reaction with the vinylcerium reagent providing alcohol 14, elongation of the side chain with b-configuration was conducted prior to the semi-pinacol rearrangement reaction. Thus, reduction of the cyano group with diisobutylaluminum hydride (DIBAH) afforded the corresponding aldehyde that in turn was reacted with (methoxymethylene) triphenylphosphorane to give enol ether 15. Stereoselective oxidation to epoxide 16 followed by the semi-pinacol rearrangement promoted by TMSOTf and 2,6-lutidine led to the formation of ketone 17 without affecting the enol ether moiety. Treatment of 17 with pyridinium p-toluenesulfonate (PPTS) in MeOH effected formation of the acetal moiety and removal of the TMS group, and the resulting alcohol was protected with a methoxymethyl (MOM) group to yield 18. Having the desired trans-hydrindane derivative with two quaternary asymmetric carbon atoms at the angular positions in hand, the stage was set for the stereoselective construction of the c-lactone moiety (Scheme 4). With a view to achieving 1,2-transposition of the cyclopentanone moiety, ketone 18 was converted to ketol 20 through the Rubottom reaction5 of enol silyl ether 19. On refluxing in toluene with Al(OiPr)3,6 ketol 20 afforded a mixture of 20 and its isomer 21 which was easily separated by silica gel chromatography. The hydroxyl group of 21 was then removed by reduction of the corresponding acetate with SmI2.7 Finally, ketone 22 was transformed into the right-hand segment of tubiferal A as shown in Scheme 5. Keto acid 23, which was obtained through hydrolysis of acetal 22 followed by the Pinnick
Scheme 4. 1,2-Transposition of the cyclopentanone moiety.
Scheme 5. Synthesis of lactone 10, the right-hand segment of tubiferal A.
T. Hiramatsu et al. / Tetrahedron Letters 55 (2014) 1145–1147
oxidation,8 was reduced with NaBH4 in the presence of CeCl3 in MeOH to afford a 4:1 mixture of epimers. The hydride attack occurred mainly from the opposite face of the acetic acid side chain, and c-lactone 25 was obtained after acidic workup. It is noteworthy that the minor epimer 24, which failed to form the corresponding c-lactone under acidic conditions, was removed simply by treating with an aqueous NaHCO3 solution. The homoprenyl chain was then introduced by successive treatment of lactone 25 with lithium diisopropylamide (LDA), hexamethylphosphoric triamide (HMPA), and 5-iodo-2-methyl-2pentene. Although the reaction afforded the undesired epimer 26 through alkylation from the convex face of the lactone moiety, regeneration of the enolate9 followed by protonation with methyl salicylate10,11 led to formation of the desired isomer 10.12 In conclusion, we have achieved the asymmetric synthesis of the right-hand segment of tubiferal A. The semi-pinacol rearrangement of an epoxy alcohol was employed for the construction of the trans-hydrindane skeleton with two quaternary stereogenic carbon atoms at the angular positions. We are currently exploring the method for the stereoselective construction of the left-hand moiety of tubiferal A. Acknowledgments This work was partially supported by the Global COE Program (Project No. B01: Catalysis as the Basis for Innovation in Materials Science) and Grant-in-Aid for Scientific Research on Innovative Areas (Project No. 2105: Organic Synthesis Based on Reaction Integration) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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References and notes 1. Kamata, K.; Onuki, H.; Hirota, H.; Yamamoto, Y.; Hayashi, M.; Komiyama, K.; Sato, M.; Ishibashi, M. Tetrahedron 2004, 60, 9835–9839. 2. Tanino, K.; Takahashi, M.; Tomata, Y.; Tokura, H.; Uehara, T.; Narabu, T.; Miyashita, M. Nat. Chem. 2011, 3, 484–488. 3. (a) Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.; Shimazaki, M.; Tsuchihashi, G. J. Am. Chem. Soc. 1986, 108, 3827–3829; (b) Suzuki, K.; Miyazawa, M.; Shimazaki, M.; Tsuchihashi, G. Tetrahedron Lett. 1986, 27, 6237– 6240. 4. Tanino, K.; Tomata, Y.; Shiina, Y.; Miyashita, M. Eur. J. Org. Chem. 2006, 328– 334. 5. Rubottom, G. M.; Gruber, J. M. J. Org. Chem. 1978, 43, 1599–1602. 6. Paquette, L. A.; Hofferberth, J. E. Org. React. 2003, 62, 477–567. 7. Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 1135–1138. 8. (a) Kuras, G. A.; Roth, B. J. Org. Chem. 1980, 45, 4825–4830; (b) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981, 37, 2091–2096. 9. We found that the enolate was gradually decomposed when the reaction was allowed to warm up from 78 °C to 50 °C. 10. Krause, N. Angew. Chem., Int. Ed. 1994, 33, 1764–1765. 11. The desired isomer 10 was formed as a sole product, while the chemical yield was not so high. On the other hand, the use of acetic acid instead of methyl salicylate gave a 4:1 mixture of 10 and 26. 12. Spectral data for 10: ½a26 D 12.28 (c 0.09, CH2Cl2); IR (neat) 3080, 2926, 2871, 2855, 1771, 1627, 1466, 1449, 1377, 1152, 1193, 1036, 970, 919, 846, 805 cm1. 1H NMR (500 MHz, CDCl3) d 6.26 (1H, dd, J = 17.0, 11.0 Hz), 5.14 (1H, d, J = 11.0 Hz), 5.12 (1H, d, J = 17.0 Hz), 5.09 (1H, t, J = 6.5 Hz), 4.68 (1H, ddd, J = 8.0, 7.5, 5.0 Hz), 4.63 (1H, d, J = 7.0 Hz), 4.54 (1H, d, J = 7.0 Hz), 3.54 (1H, t, J = 2.5 Hz), 3.37 (3H, s), 2.61 (1H, ddd, J = 8.0, 7.5, 5.0 Hz), 2.44 (1H, dd, J = 8.0, 7.5 Hz), 2.34 (1H, dd, J = 13.5, 7.0 Hz), 2.28 (1H, dd, J = 13.5, 5.0 Hz), 2.15 (1H, dd, J = 14.0, 7.5 Hz), 2.00 (1H, m), 1.87 (1H, m), 1.71–1.65 (5H, m, involving a singlet at 1.70), 1.64–1.49 (8H, m, involving a singlet at 1.62), 1.22 (3H, s); 13C NMR (125 MHz, CDCl3) d 179.43, 142.35, 133.03, 123.42, 115.31, 95.84, 81.61, 79.47, 55.56, 55.16, 50.17, 44.55, 42.89, 34.01, 31.53, 29.72, 27.17, 25.78, 25.20, 18.14, 17.85, 16.96.; HRMS (FD) calcd for C22H34O4 (M+): 362.24571, found 362.24677.