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Chemoenzymatic total synthesis of four stereoisomers of centrolobine
Tetrahedron Letters 56 (2015) 4916–4918
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Chemoenzymatic total synthesis of four stereoisomers of centrolobine Bollipalli Nagarjuna b, Barla Thirupathi a, Chunduri Venkata Rao b, Debendra K. Mohapatra a,⇑ a b
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 5000 007, India Chemistry Department, Sri Venkateswara University, Tirupati, Andhra Pradesh 517502, India
a r t i c l e
i n f o
Article history: Received 22 May 2015 Revised 18 June 2015 Accepted 26 June 2015 Available online 30 June 2015 Keywords: Centrolobine Tetrahydropyran ring Enzymatic resolution Cross-metathesis Tandem isomerization followed by C–O and C–C bond formation reaction
a b s t r a c t Four stereoisomers of centrolobine, (3R,7S)-( )-centrolobine (1), (3S,7S)-( )-epi-centrolobine (2), (3S,7R)-(+)-centrolobine (3), and (3R,7R)-(+)-epi-centrolobine (4) have been achieved in an efficient manner in 24–28% overall yield over 9–10 linear steps starting from cheap and commercially available 4-methoxybenzaldehyde following chemoenzymatic protocol. The key features of this synthetic protocol are enzymatic resolution, cross-metathesis (CM), and our own developed tandem isomerization followed by C–O and C–C bond formation reaction. Ó 2015 Elsevier Ltd. All rights reserved.
Centrolobine is a naturally occurring heterocyclic compound, bearing a six-membered tetrahydropyran ring system usually with a syn stereochemistry in the alkyl substituents on both carbons flanking the ether linkage, was (3S,7R)-(+)-centrolobine ((3S,7R)-3) obtained from the closely related species Centrolobine robustum1 whereas its enantiomer the laevorotatory (3R,7S)-( )-centrolobine ((3R,7S)-1) isolated from the heartwood of Centrolobium tomentosum, mostly found in the amazon rain forest and again from the stem of Brosimum potabile in 2000.2 It has been shown to be active against Leishmania amazonensis promastigotes; a parasite associated with leishmaniasis, a major health problem in Brazil.3 Leishmania is a parasitic disease transmitted by the sand fly, this parasite attacks the spongiform organs of the body, especially the liver and spleen. Centrolobines have also been found to exhibit anti-inflammatory properties.3a,b Although the basic structure was elucidated in 1964 by total synthesis of the racemic methyl ether,1a,b its absolute configuration was established by Solladié and Carreño in 2002 by an enantioselective total syntheis.4 The excellent bioactivities and relatively simple chemical structure have attracted considerable attention and several research groups have accomplished the total synthesis of centrolobine.5,6 In 2009, Hölter and Schmidt only described the total synthesis of all stereoisomers of the natural product by using enantioselective
⇑ Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512. E-mail address: [email protected] (D.K. Mohapatra). http://dx.doi.org/10.1016/j.tetlet.2015.06.084 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
allylation with enantiomerically pure allylsilanes, a tandem ringclosing metathesis-isomerization reactions.5rAs a part of an ongoing program in exploring tandem isomerization followed by C–O and C–C bond formation reaction protocol for the synthesis of pyran ring-containing complex natural products such as bicyclic core of penostatin B,7a (+)-sorangicin A,7h polyrachitides,7f,b the macrolactone core of leucascandrolide A,7g Z-isomers of the proposed and revised aspergillide B7d and formal total synthesis of cladosporin,7e herein, we demonstrated the use of our above novel strategy for the total synthesis of all possible isomers of centrolobine (see Fig. 1). According to our retrosynthetic analysis of (3R,7S)-( )centrolobine ((3R,7S)-1) and (3S,7S)-( )-epi-centrolobine ((3S,7S)-2) as shown in Scheme 1, both the compounds could be achieved from ketone intermediates 5, which in turn could be prepared from trans-2,6-disubstituted dihydropyran 6. Dihydropyran 6 in turn could be obtained by domino isomerization followed by C–O and C–C bond formation reaction of d-hydroxy a,b-unsaturated aldehyde 7 which could be prepared from homoallyl alcohol 8 by following cross-metathesis reaction. Alcohol 8 could be synthesized from 4-methoxy benzaldehyde (9) through Grignard reaction and enzymatic resolution of resulting racemic alcohol. The synthesis of the crucial intermediate 6 was started from racemic alcohol 10 which was subjected for enzymatic resolution with Amano lipase PS-C II8 to obtain homoallylic alcohol 8 with 99% ee (by HPLC) and acetate derivative 11. Following a modified Mosher ester method,9 the stereogenic center in compound 15
4917
B. Nagarjuna et al. / Tetrahedron Letters 56 (2015) 4916–4918
O
O H
H
H
MeO
OH
H
MeO
(3R,7S)-(-)-Centrolobine (1)
OH
MeO
OH
MgBr
CHO
CuI, THF, -10 o C MeO 3 h, 92%
9
(3S,7S)-(-)-epi-Centrolobine (2)
PS-C(`Amano` II) enzyme, 4 days MTBE, 92%
10 OH
OAc
Acrolein Hoveda-Grubbs
+ O H
H
MeO
OH (3S,7R)-(+)-Centrolobine (3)
11
H
12 h, rt, 84%
MeO
MeO
O
H
8
seperated by column chromatography
MeO OH (3R,7R)-(+)-epi-Cetnrolobine (4) OH
O
Figure 1. Structures of four stereoisomers of centrolobine.
SiMe3 H
O I2, 45 min, 91%
H
H 6
MeO
7
MeO
Scheme 2. Synthesis of dihydropyran 6. O H MeO
2
H OH NaIO 4, OsO4 2,6-lutidine
5 6
4 3
7
O H MeO
1
2
O
O
1
H MeO
O
H
H OH
5
MeO
6
H
MeO
7
O O H MeO
6
H
H
2. 1N HCl 0 o C-rt 79% over two steps
CHO H
MeO
8
OH
13
H2 , PtO2 MeOH
H OH
14
0 o C-rt, 4 h, 90%
H
MeO
O MeO
MeO
DMP, CH2 Cl2
O
O OH
O 12
OH
THF, 0 o C-rt H
H
OH 1. 4-OTHPPhMgBr
OH
O H
1,4-dioxane–H2 O (3:1) MeO 0 °C, 3 h, 87%
H
rt, 12 h 89%
O O H
MeO
H OH
5
9
Scheme 3. Synthesis of ketone 5. Scheme 1. Retrosynthetic analysis of centrolobine.
bearing the secondary hydroxyl group was assigned. After having enantiomerically pure alcohol compound 8, it was then subjected to cross-metathesis with acrolein in presence of catalytic amount of Hoveyda–Grubbs10 to afford d-hydroxy a,b-unsaturated aldehyde 7 in 84% yield. Now, the stage is set to conduct our own developed tandem isomerization followed by C–O and C–C bond formation reaction.7f Accordingly, d-hydroxy a,b-unsaturated aldehyde 7 was treated with allyltrimethylsilane and catalytic amount (10 mol %) of iodine in THF to furnish trans-2,6disubstituted dihydropyran compound 6 in 91% yield as a single isomer (Scheme 2). The terminal double bond present in compound 6 was converted to aldehyde via Jin’s one-step dihydroxylation–oxidation sequence to produce aldehyde 12 in 87% yield (over two steps).11 Aldehyde 12 was subjected to Grignard reaction with THP-protected 4-hydroxyphenylmagnesium bromide in THF to obtain secondary alcohol as a 1:1 diastereomeric mixture. An acidic workup of the reaction mixture resulted in THP deprotection of the phenolic hydroxy function to afford alcohol 13 in 79% yield over two steps. The secondary hydroxy group present in 13 was oxidized by Dess–Martin periodinane (DMP),12 which smoothly produced ketone 14 in 90% yield (Scheme 3). Compound 14 was then subjected to catalytic hydrogenation with platinum(IV) oxide to produce compound 5 in 89% yield. At this stage, we thought of epimerizing trans-pyran to cis-pyran so that it will produce the natural product (3R,7S)-( )-centrolobine ((3R,7S)-1). Compound 5 was then subjected to epimerization in the presence of benzoic acid in CHCl3 under Keinan’s conditions,13 to obtain the cis product in 94% yield and the resulting epimerized product on treatment with Pd/C under hydrogen atmosphere
following a reported protocol5z resulted in the formation of (3R,7S)-( )-centrolobine ((3R,7S)-1). Similarly, palladiumcatalyzed reduction of ketone 5 without epimerization furnished (3S,7S)-( )-epi-centrolobine (2) (Scheme 4). The spectral and analytical data for the synthetic compound (3R,7S)-( )centrolobine (1) and (3S,7S)-( )-epi-centrolobine (2) were in good agreement with the data reported.5r After achieving the synthesis of (3R,7S)-( )-centrolobine (1) and (3S,7S)-( )-epi-centrolobine (2), we next focused our research for the synthesis of other two isomers starting from acetylated compound 10 obtained through enzymatic resolution. The acetyl compound 10 was easily saponified by K2CO3 in methanol to afford homoallyl alcohol 15 in 88% yield, which became the starting precursor for the synthesis of (3S,7R)-(+)-centrolobine (3) and (3R,7R)-(+)-epi-centrolobine (4). Compound 21 O
MeO
O H 5 H
OH
Pd/C, H 2 , HCl EtOH/EtOAc/H 2O (4:1:1), 10 h, 71%
2. Pd/C, H 2, HCl EtOH/EtOAc/H 2O (4:1:1), 10 h, 73%
1. PhCO 2H, CHCl3 rt., 2 days 94%
O
O H
H
H
MeO
OH (3R,7S)-Cetrolobine (1)
H
MeO
OH
(3S,7S)-(-)-epi-Centrolobine (2)
Scheme 4. Synthesis of (3R,7S)-( )-centrolobine (1) and (3S,7S)-( )-epi-centrolobine (2).
4918
B. Nagarjuna et al. / Tetrahedron Letters 56 (2015) 4916–4918
Acknowledgments
OH
OAc K2CO3 , MeOH MeO
0 o C-rt, 4 h 88%
11
OH
B.N. and B.T. thank the University Grants Commission (UGC), New Delhi, India for financial assistance in the form of fellowships. D.K.M. thanks the CSIR, New Delhi, India, for financial support as part of XII Five Year plan programme under title ORIGIN (CSC-0108).
MeO 15
O
Acrolein
SiMe3 H
12 h, rt, 86%
I2, 45 min, 92%
16
MeO
Supplementary data
NaIO4 , OsO4 2,6-lutidine MeO
17
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.06.084.
O
O H
H
H
1,4-dioxane–H2 O (3:1) 0 °C, 3 h, 86% MeO
18
H O
References and notes OH
1. 4-OTHPPhMgBr THF, 0 oC-rt
DMP, CH2 Cl2 O
2. 1N HCl 0 oC-rt MeO 78% over two steps
H
H 20
OH
O
H 2, PtO 2 MeOH
O H
0 C-rt, 4 h, 91%
H 19
O
MeO
o
O H
rt, 12 h OH 87% MeO
H 21
OH
Scheme 5. Synthesis of ketone 21.
O O H MeO
1. PhCO 2H, CHCl3 rt, 2 days, 95%
21
H OH
Pd/C, H2 , HCl EtOH/EtOAc/H 2O (4:1:1), 10 h, 70%
2. Pd/C, H 2, HCl EtOH/EtOAc/H 2O (4:1:1), 10 h, 72%
O H
O
H
MeO
H
H
OH MeO (3S,7R)-(+)-Centrolobine (3)
OH
(3R,7R)-(+)-epi-Cetnrolobine (4)
Scheme 6. Synthesis of (3S,7R)-(+)-centrolobine (3) and (3R,7R)-(+)-epi-centrolobine (4).
was obtained starting from homoallyl alcohol 15 through the same sequence of reactions as shown in Schemes 2 and 3 in good overall yield (Scheme 5). As earlier mentioned, compound 21 was then subjected to epimerization in the presence of benzoic acid in CHCl3 under Keinan’s conditions,13 to obtain the epimerized product in 95% yield followed by palladium-catalyzed5z reduction of ketone, resulted in the formation of (3S,7R)-(+)-centrolobine (3). Similarly, palladium-catalyzed5z reduction of ketone 21 directly afforded (3R,7R)-(+)-epi-centrolobine (4) (Scheme 6). The synthesized compounds (3S,7R)-(+)-centrolobine (3) and (3R,7R)(+)-epi-centrolobine (4) were characterized by their spectral and analytical data and were in good agreement with the reported values.5r In summary, we have accomplished the synthesis of four stereoisomers of centrolobine following chemoenzymatic resolution, domino isomerization followed by C–O and C–C bond formation reaction, cross-metathesis as key reactions, starting from 4-methoxy benzaldehyde. Our protocol is highly flexible and with good overall yield for the synthesis of four stereoisomers of centrolobine compared to previous reports.
1. (a) De Albuquerque, I. L.; Galeffi, C.; Casinovi, C. G.; Marini-Bettolo, G. B. Gazz. Chim. Ital. 1964, 287; (b) Galeffi, C.; Casinovi, C. G.; Marini-Bettòlo, G. B. Gazz. Chim. Ital. 1965, 95; (c) Craveiro, A. A. Phytochemistry 1970, 9, 1869. 2. (a) Jurd, L.; Wong, R. Y. Aust. J. Chem. 1984, 37, 1127; (b) de C. Alcantara, A. F.; Souza, M. R.; Pilo9 -Veloso, D. Fitoterapia 2000, 71, 613; (c) Alegrio, L. V.; BrazFilho, R.; Gottlieb, O. R. Phytochemistry 1989, 28, 2359. 3. (a) Araujo, C. A. C.; Alegrio, L. V.; Leon, L. L. Phytochemistry 1998, 49, 751; (b) Araujo, C. A. C.; Alegrio, L. V.; Gomes, D. C. F.; Lima, M. E. F. Mem. Inst. Oswaldo Cruz. 1999, 94, 791. 4. Colobert, F.; Mazery, R. D.; Solladie, G.; Carreño, M. C. Org. Lett. 2002, 4, 1723. 5. (a) Latif, M.; Yun, J. I.; Seshadri, K.; Kim, H. R.; Park, C. H.; Park, H.; Kim, H.; Lee, J. J. Org. Chem. 2015, 80, 3315; (b) Yang, Z.; Kim, H.-D. Tetrahedron: Asymmetry 2014, 25, 305; (c) Zeng, J.; Tan, Y. J.; Ma, J. Chem. Eur. J. 2014, 20, 405; (d) Sudarshanand, K.; Aidhen, I. S. Eur. J. Org. Chem. 2013, 2298; (e) Kumaraswamy, G.; Rambabu, D. Tetrahedron: Asymmetry 2013, 24, 196; (f) Xie, J.-H.; Guo, L.-C.; Yang, X.-H.; Wang, L.-X.; Zhou, Q.-L. Org. Lett. 2012, 14, 4758; (g) Ahmed, N.; Konduru, N. K. Beilstein J. Org. Chem. 2012, 8, 177; (h) Fujioka, H.; Yahata, K.; Kubo, O.; Sawama, Y.; Hamada, T.; Maegawa, T. Angew. Chem., Int. Ed. 2011, 50, 12232; (i) Schmidt, B.; Hölter, F.; Kelling, A. J. Org. Chem. 2011, 76, 3357; (j) Clarke, P. A.; Sellars, P. B.; Mistry, N. Tetrahedron Lett. 2011, 52, 3654; (k) Iqbal, M.; Mistry, N.; Clarke, P. A. Tetrahedron 2011, 67, 4960; (l) Jeong, Y.; Kim, D.-Y.; Choi, Y.; Ryu, J.-S. Org. Biomol. Chem. 2011, 9, 374; (m) Reddy, C. R.; Madhavi, P. P.; Chandrasekhar, S. Synthesis 2011, 1, 123; (n) Schmidt, B.; Berger, R.; Hölter, F. Org. Biomol. Chem. 2010, 8, 1406; (o) Reddy, C. R.; Madhavi, P. P.; Chandrasekhar, S. Tetrahedron: Asymmetry 2010, 21, 103; (p) Chazadaj, W.; Kowalczyk, R.; Jurczak, J. J. Org. Chem. 2010, 75, 1740; (q) Haruhiko, F.; Kenkichi, N.; Makoto, S. Heterocycles 2010, 82, 641; (r) Mohapatra, D. K.; Pal, R.; Rahaman, H.; Gurjar, M. K. Heterocycles 2010, 1, 219; (s) Schmidt, B.; Hölter, F. Chem. Eur. J. 2009, 15, 11948; (t) Takeuchi, T.; Matsuhashi, M.; Nakata, T. Tetrahedron Lett. 2008, 49, 6462; (u) Dziedzic, M.; Furman, B. Tetrahedron Lett. 2008, 49, 678; (v) Prasad, K. Tetrahedron 2007, 63, 1089; (w) Washio, T.; Yamaguchi, R.; Abe, T.; Nambu, H.; Anada, M.; Hashimoto, S. Tetrahedron 2007, 63, 12037; (x) Böhrsch, V.; Blechert, S. Chem. Commun. 2006, 1968; (y) Lee, A. C.-H. Tetrahedron Lett. 2006, 47, 1641; (z) Clarke, P. A.; Santos, S. Tetrahedron Lett. 2005, 46, 6651. 6. (a) Jennings, M. P.; Clemens, R. T. Tetrahedron Lett. 2005, 46, 2021; (b) Clarke, P. A.; Martin, W. H. C. Tetrahedron 2005, 61, 5433; (c) Lee, E.; Kim, H. J.; Jang, W. S. Bull. Korean Chem. Soc. 2004, 25, 1609; (d) Evans, P. A.; Cui, J.; Gharpure, S. J. Org. Lett. 2003, 5, 3883; (e) Colobert, F.; Carreño, M. C.; Mazery, R. D.; Urbano, A.; Colobert, F.; Solladie, G. J. Org. Chem. 2003, 68, 7779; (f) Mazery, R. D.; Solladie, G.; Carreño, M. C. Org. Lett. 2002, 4, 1723; (g) Marumoto, S. Org. Lett. 2002, 4, 3919. 7. (a) Reddy, D. S. J. Org. Chem. 2015, 80, 1365; (b) Padhi, B.; Reddy, D. S.; Mohapatra, D. K. Eur. J. Org. Chem. 2015, 542; (c) Mohapatra, D. K.; Krishnarao, P. S.; Bhimireddy, E.; Yadav, J. S. Synthesis 2014, 46, 1639; (d) Pradhan, T. R.; Das, P. P.; Mohapatra, D. K. Synthesis 2014, 46, 1177; (e) Mohapatra, D. K.; Maity, S.; Rao, T. S.; Yadav, J. S.; Sridhar, B. Eur. J. Org. Chem. 2013, 2859; (f) Mohapatra, D. K.; Bhimireddy, E.; Krishnarao, P. S.; Das, P. P.; Yadav, J. S. Org. Lett. 2011, 13, 744; (g) Yadav, J. S.; Pattanayak, M. R.; Das, P. P.; Mohapatra, D. K. Org. Lett. 2011, 13, 1710; (h) Mohapatra, D. K.; Das, P. P.; Pattanayak, M. R.; Yadav, J. S. Chem. Eur. J. 2010, 16, 2072. 8. (a) Roberts, S. M. Biocatalysts for Fine Chemicals Synthesis; John Wiley & Sons: Chichester, 1999; (b) Jaeger, K.-E.; Reetz, M. T. Trends Biotechnol. 1998, 16, 396; (c) Silverman, R. B. The Organic Chemistry of Enzyme-Catalyzed Reactions; Academic Press: USA, 2000; (d) Roberts, S. M. J. Chem. Soc., Perkin Trans. 1 2001, 1475; (e) Carrea, G.; Riva, S. Angew. Chem., Int. Ed. 2000, 39, 2226; (f) Singh, S.; Kumar, S.; Chimni, S. Tetrahedron: Asymmetry 2002, 13, 2679. 9. (a) Ohtani, I.; Kusumi, J.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092; (b) Yoshida, W. Y.; Bryan, P. J.; Baker, B. J.; McClintock, J. B. J. Org. Chem. 1995, 60, 780. 10. (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168; (b) Dinh, M.-T.; Bouzbouz, S.; Peglion, J. L.; Cossy, J. Tetrahedron 2008, 64, 5703. 11. Yu, W.; Mei, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217. 12. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155; (b) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277. 13. Keinan, E.; Seth, K. K.; Lamed, R. J. Am. Chem. Soc. 1986, 108, 3474.
Contents lists available at ScienceDirect
Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Chemoenzymatic total synthesis of four stereoisomers of centrolobine Bollipalli Nagarjuna b, Barla Thirupathi a, Chunduri Venkata Rao b, Debendra K. Mohapatra a,⇑ a b
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 5000 007, India Chemistry Department, Sri Venkateswara University, Tirupati, Andhra Pradesh 517502, India
a r t i c l e
i n f o
Article history: Received 22 May 2015 Revised 18 June 2015 Accepted 26 June 2015 Available online 30 June 2015 Keywords: Centrolobine Tetrahydropyran ring Enzymatic resolution Cross-metathesis Tandem isomerization followed by C–O and C–C bond formation reaction
a b s t r a c t Four stereoisomers of centrolobine, (3R,7S)-( )-centrolobine (1), (3S,7S)-( )-epi-centrolobine (2), (3S,7R)-(+)-centrolobine (3), and (3R,7R)-(+)-epi-centrolobine (4) have been achieved in an efficient manner in 24–28% overall yield over 9–10 linear steps starting from cheap and commercially available 4-methoxybenzaldehyde following chemoenzymatic protocol. The key features of this synthetic protocol are enzymatic resolution, cross-metathesis (CM), and our own developed tandem isomerization followed by C–O and C–C bond formation reaction. Ó 2015 Elsevier Ltd. All rights reserved.
Centrolobine is a naturally occurring heterocyclic compound, bearing a six-membered tetrahydropyran ring system usually with a syn stereochemistry in the alkyl substituents on both carbons flanking the ether linkage, was (3S,7R)-(+)-centrolobine ((3S,7R)-3) obtained from the closely related species Centrolobine robustum1 whereas its enantiomer the laevorotatory (3R,7S)-( )-centrolobine ((3R,7S)-1) isolated from the heartwood of Centrolobium tomentosum, mostly found in the amazon rain forest and again from the stem of Brosimum potabile in 2000.2 It has been shown to be active against Leishmania amazonensis promastigotes; a parasite associated with leishmaniasis, a major health problem in Brazil.3 Leishmania is a parasitic disease transmitted by the sand fly, this parasite attacks the spongiform organs of the body, especially the liver and spleen. Centrolobines have also been found to exhibit anti-inflammatory properties.3a,b Although the basic structure was elucidated in 1964 by total synthesis of the racemic methyl ether,1a,b its absolute configuration was established by Solladié and Carreño in 2002 by an enantioselective total syntheis.4 The excellent bioactivities and relatively simple chemical structure have attracted considerable attention and several research groups have accomplished the total synthesis of centrolobine.5,6 In 2009, Hölter and Schmidt only described the total synthesis of all stereoisomers of the natural product by using enantioselective
⇑ Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512. E-mail address: [email protected] (D.K. Mohapatra). http://dx.doi.org/10.1016/j.tetlet.2015.06.084 0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
allylation with enantiomerically pure allylsilanes, a tandem ringclosing metathesis-isomerization reactions.5rAs a part of an ongoing program in exploring tandem isomerization followed by C–O and C–C bond formation reaction protocol for the synthesis of pyran ring-containing complex natural products such as bicyclic core of penostatin B,7a (+)-sorangicin A,7h polyrachitides,7f,b the macrolactone core of leucascandrolide A,7g Z-isomers of the proposed and revised aspergillide B7d and formal total synthesis of cladosporin,7e herein, we demonstrated the use of our above novel strategy for the total synthesis of all possible isomers of centrolobine (see Fig. 1). According to our retrosynthetic analysis of (3R,7S)-( )centrolobine ((3R,7S)-1) and (3S,7S)-( )-epi-centrolobine ((3S,7S)-2) as shown in Scheme 1, both the compounds could be achieved from ketone intermediates 5, which in turn could be prepared from trans-2,6-disubstituted dihydropyran 6. Dihydropyran 6 in turn could be obtained by domino isomerization followed by C–O and C–C bond formation reaction of d-hydroxy a,b-unsaturated aldehyde 7 which could be prepared from homoallyl alcohol 8 by following cross-metathesis reaction. Alcohol 8 could be synthesized from 4-methoxy benzaldehyde (9) through Grignard reaction and enzymatic resolution of resulting racemic alcohol. The synthesis of the crucial intermediate 6 was started from racemic alcohol 10 which was subjected for enzymatic resolution with Amano lipase PS-C II8 to obtain homoallylic alcohol 8 with 99% ee (by HPLC) and acetate derivative 11. Following a modified Mosher ester method,9 the stereogenic center in compound 15
4917
B. Nagarjuna et al. / Tetrahedron Letters 56 (2015) 4916–4918
O
O H
H
H
MeO
OH
H
MeO
(3R,7S)-(-)-Centrolobine (1)
OH
MeO
OH
MgBr
CHO
CuI, THF, -10 o C MeO 3 h, 92%
9
(3S,7S)-(-)-epi-Centrolobine (2)
PS-C(`Amano` II) enzyme, 4 days MTBE, 92%
10 OH
OAc
Acrolein Hoveda-Grubbs
+ O H
H
MeO
OH (3S,7R)-(+)-Centrolobine (3)
11
H
12 h, rt, 84%
MeO
MeO
O
H
8
seperated by column chromatography
MeO OH (3R,7R)-(+)-epi-Cetnrolobine (4) OH
O
Figure 1. Structures of four stereoisomers of centrolobine.
SiMe3 H
O I2, 45 min, 91%
H
H 6
MeO
7
MeO
Scheme 2. Synthesis of dihydropyran 6. O H MeO
2
H OH NaIO 4, OsO4 2,6-lutidine
5 6
4 3
7
O H MeO
1
2
O
O
1
H MeO
O
H
H OH
5
MeO
6
H
MeO
7
O O H MeO
6
H
H
2. 1N HCl 0 o C-rt 79% over two steps
CHO H
MeO
8
OH
13
H2 , PtO2 MeOH
H OH
14
0 o C-rt, 4 h, 90%
H
MeO
O MeO
MeO
DMP, CH2 Cl2
O
O OH
O 12
OH
THF, 0 o C-rt H
H
OH 1. 4-OTHPPhMgBr
OH
O H
1,4-dioxane–H2 O (3:1) MeO 0 °C, 3 h, 87%
H
rt, 12 h 89%
O O H
MeO
H OH
5
9
Scheme 3. Synthesis of ketone 5. Scheme 1. Retrosynthetic analysis of centrolobine.
bearing the secondary hydroxyl group was assigned. After having enantiomerically pure alcohol compound 8, it was then subjected to cross-metathesis with acrolein in presence of catalytic amount of Hoveyda–Grubbs10 to afford d-hydroxy a,b-unsaturated aldehyde 7 in 84% yield. Now, the stage is set to conduct our own developed tandem isomerization followed by C–O and C–C bond formation reaction.7f Accordingly, d-hydroxy a,b-unsaturated aldehyde 7 was treated with allyltrimethylsilane and catalytic amount (10 mol %) of iodine in THF to furnish trans-2,6disubstituted dihydropyran compound 6 in 91% yield as a single isomer (Scheme 2). The terminal double bond present in compound 6 was converted to aldehyde via Jin’s one-step dihydroxylation–oxidation sequence to produce aldehyde 12 in 87% yield (over two steps).11 Aldehyde 12 was subjected to Grignard reaction with THP-protected 4-hydroxyphenylmagnesium bromide in THF to obtain secondary alcohol as a 1:1 diastereomeric mixture. An acidic workup of the reaction mixture resulted in THP deprotection of the phenolic hydroxy function to afford alcohol 13 in 79% yield over two steps. The secondary hydroxy group present in 13 was oxidized by Dess–Martin periodinane (DMP),12 which smoothly produced ketone 14 in 90% yield (Scheme 3). Compound 14 was then subjected to catalytic hydrogenation with platinum(IV) oxide to produce compound 5 in 89% yield. At this stage, we thought of epimerizing trans-pyran to cis-pyran so that it will produce the natural product (3R,7S)-( )-centrolobine ((3R,7S)-1). Compound 5 was then subjected to epimerization in the presence of benzoic acid in CHCl3 under Keinan’s conditions,13 to obtain the cis product in 94% yield and the resulting epimerized product on treatment with Pd/C under hydrogen atmosphere
following a reported protocol5z resulted in the formation of (3R,7S)-( )-centrolobine ((3R,7S)-1). Similarly, palladiumcatalyzed reduction of ketone 5 without epimerization furnished (3S,7S)-( )-epi-centrolobine (2) (Scheme 4). The spectral and analytical data for the synthetic compound (3R,7S)-( )centrolobine (1) and (3S,7S)-( )-epi-centrolobine (2) were in good agreement with the data reported.5r After achieving the synthesis of (3R,7S)-( )-centrolobine (1) and (3S,7S)-( )-epi-centrolobine (2), we next focused our research for the synthesis of other two isomers starting from acetylated compound 10 obtained through enzymatic resolution. The acetyl compound 10 was easily saponified by K2CO3 in methanol to afford homoallyl alcohol 15 in 88% yield, which became the starting precursor for the synthesis of (3S,7R)-(+)-centrolobine (3) and (3R,7R)-(+)-epi-centrolobine (4). Compound 21 O
MeO
O H 5 H
OH
Pd/C, H 2 , HCl EtOH/EtOAc/H 2O (4:1:1), 10 h, 71%
2. Pd/C, H 2, HCl EtOH/EtOAc/H 2O (4:1:1), 10 h, 73%
1. PhCO 2H, CHCl3 rt., 2 days 94%
O
O H
H
H
MeO
OH (3R,7S)-Cetrolobine (1)
H
MeO
OH
(3S,7S)-(-)-epi-Centrolobine (2)
Scheme 4. Synthesis of (3R,7S)-( )-centrolobine (1) and (3S,7S)-( )-epi-centrolobine (2).
4918
B. Nagarjuna et al. / Tetrahedron Letters 56 (2015) 4916–4918
Acknowledgments
OH
OAc K2CO3 , MeOH MeO
0 o C-rt, 4 h 88%
11
OH
B.N. and B.T. thank the University Grants Commission (UGC), New Delhi, India for financial assistance in the form of fellowships. D.K.M. thanks the CSIR, New Delhi, India, for financial support as part of XII Five Year plan programme under title ORIGIN (CSC-0108).
MeO 15
O
Acrolein
SiMe3 H
12 h, rt, 86%
I2, 45 min, 92%
16
MeO
Supplementary data
NaIO4 , OsO4 2,6-lutidine MeO
17
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.06.084.
O
O H
H
H
1,4-dioxane–H2 O (3:1) 0 °C, 3 h, 86% MeO
18
H O
References and notes OH
1. 4-OTHPPhMgBr THF, 0 oC-rt
DMP, CH2 Cl2 O
2. 1N HCl 0 oC-rt MeO 78% over two steps
H
H 20
OH
O
H 2, PtO 2 MeOH
O H
0 C-rt, 4 h, 91%
H 19
O
MeO
o
O H
rt, 12 h OH 87% MeO
H 21
OH
Scheme 5. Synthesis of ketone 21.
O O H MeO
1. PhCO 2H, CHCl3 rt, 2 days, 95%
21
H OH
Pd/C, H2 , HCl EtOH/EtOAc/H 2O (4:1:1), 10 h, 70%
2. Pd/C, H 2, HCl EtOH/EtOAc/H 2O (4:1:1), 10 h, 72%
O H
O
H
MeO
H
H
OH MeO (3S,7R)-(+)-Centrolobine (3)
OH
(3R,7R)-(+)-epi-Cetnrolobine (4)
Scheme 6. Synthesis of (3S,7R)-(+)-centrolobine (3) and (3R,7R)-(+)-epi-centrolobine (4).
was obtained starting from homoallyl alcohol 15 through the same sequence of reactions as shown in Schemes 2 and 3 in good overall yield (Scheme 5). As earlier mentioned, compound 21 was then subjected to epimerization in the presence of benzoic acid in CHCl3 under Keinan’s conditions,13 to obtain the epimerized product in 95% yield followed by palladium-catalyzed5z reduction of ketone, resulted in the formation of (3S,7R)-(+)-centrolobine (3). Similarly, palladium-catalyzed5z reduction of ketone 21 directly afforded (3R,7R)-(+)-epi-centrolobine (4) (Scheme 6). The synthesized compounds (3S,7R)-(+)-centrolobine (3) and (3R,7R)(+)-epi-centrolobine (4) were characterized by their spectral and analytical data and were in good agreement with the reported values.5r In summary, we have accomplished the synthesis of four stereoisomers of centrolobine following chemoenzymatic resolution, domino isomerization followed by C–O and C–C bond formation reaction, cross-metathesis as key reactions, starting from 4-methoxy benzaldehyde. Our protocol is highly flexible and with good overall yield for the synthesis of four stereoisomers of centrolobine compared to previous reports.
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