- Email: [email protected]
Synthesis of caprazamycin B
Accepted Manuscript Synthesis of Caprazamycin B Hikaru Abe, Purushothaman Gopinath, Gandamala Ravi, Lu Wang, Takumi Watanabe, Masakatsu Shibasaki PII: DOI: Reference:
S0040-4039(15)00702-9 http://dx.doi.org/10.1016/j.tetlet.2015.04.065 TETL 46204
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
16 March 2015 10 April 2015 17 April 2015
Please cite this article as: Abe, H., Gopinath, P., Ravi, G., Wang, L., Watanabe, T., Shibasaki, M., Synthesis of Caprazamycin B, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.04.065
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Synthesis of Caprazamycin B
Hikaru Abe, Purushothaman Gopinath, Gandamala Ravi, Lu Wang, Takumi Watanabe*, Masakatsu Shibasaki*
Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
ABSTRACT: Caprazamycin B was successfully synthesized via caprazol. In the present synthesis, the choices of the segment coupling conditions and protecting groups were unexpectedly narrow. Only Shiina’s protocol provided the ester linkage between the unreactive secondary hydroxyl group on the diazepanone ring system and the side chain moiety (western zone). Upon final global deprotection, hydrogenolysis conditions were compatible with substructures that are unstable under acidic and basic environments.
1
(Graphical Abstract)
Keywords: Caprazamycin B; Liponucleoside-antibiotic; Natural product synthesis; Anti-tuberculosis agent
* Corresponding authors, tel.: +81 3 3441 4173; fax: +81 3 3441 7589 (T.W.); tel.: +81 3 3447 7779; fax:
+81
3
3441
7589
(M.S.);
e-mail
addresses:
[email protected] (M.S.).
2
[email protected]
(T.W.),
Caprazamycins, lipo-nucleoside antibiotics that comprise a mixture of seven constituents possessing aliphatic side chains of varying lengths and branched patterns (Figure 1), are considered as promising anti-tuberculosis (TB) natural products.1 Among them, caprazamycin B (1) exerts the most potent anti-TB activity, due mainly to the inhibition of MraY,2 a key enzyme in the peptidoglycan biosynthesis pathway of the pathogens. Subsequent semisynthetic structure-activity relationship (SAR) studies were performed using caprazamycins as starting materials to develop CPZEN-45 (2),3 an anti-XDR-TB (extensively multidrug-resistant TB) agent; XDR-TB is a TB strain that is resistant to many of the currently available clinical drugs. Notably, the mechanisms underlying the anti-XDR-TB activity of CPZEN-45 is the inhibition of WecA.2 This enzyme is involved in the biosynthesis of mycolyl arabinogalactan, which is essential for Mycobacterium tuberculosis,4 yet it has never been a molecular target of clinical anti-TB drugs. Consequently, synthetic chemical libraries in which caprazamycin derivatives are reposited are potential sources of lead compounds for urgently demanded anti-XDR-TB agents. Thereby, efficient synthetic routes to caprazamycins and related natural products5 that would enable access to their derivatives with rich structural diversity have been extensively pursued.
3
Figure 1. Caprazamycin B and related compounds.
Caprazamycins have attracted interest from the synthetic community not only for their unique biological activities, but also due to their complex molecular architecture: 19 stereogenic centers are densely furnished on the uncommon framework, including the central diazepanone moiety, and substructures susceptible to both acidic (acylglycoside linkage) and basic (β-amino-α-hydroxycarbonyl moieties) conditions are present. Indeed, tremendous effort by many research groups has been dedicated to the synthesis of caprazamycin-related natural products,6 and two total syntheses of (+)-caprazol have been disclosed to date.7,8 (+)-Caprazol (3, Figure 1) was discovered in the isolation process of caprazamycins from natural resources, and is regarded as the core structure of caprazamycins. The first total synthesis of this molecule was reported by Matsuda, Ichikawa and co-workers in 2005.7 The synthesis tactically took advantage of the Sharpless’ catalytic asymmetric aminohydroxylation and the pre-organized stereochemistry of D-serine to build the syn-β-amino-α-hydroxyamide portion at the juncture of the diazepanone and the uridine cores, and the anti-congener embedded in the diazepanone ring, 4
respectively.
Scheme 1. Synthetic strategy of caprazamycin B.
We recently completed a catalytic asymmetric total synthesis of (+)-caprazol as a part of synthetic endeavor toward caprazamycin B.8 Our approach centered on catalytic enantioselective and diastereoselective aldol-type chemistries to provide the stereo-elements required to synthesize caprazol and caprazamycin B (Scheme 1). The syn- and anti-β-amino-α-hydroxyamide substructures depicted above were constructed by a catalytic isocyanoacetate-aldol reaction (14 and 15 to 16), and an anti-selective catalytic asymmetric nitroaldol reaction developed in our laboratory (9 and 10 to 11),9 respectively. This strategy could be used to efficiently build the molecular skeleton with simultaneous installation of the correct configuration with highly stereoselective C-C bond forming reactions. In advance to the report, we also reported the catalytic asymmetric synthesis of a potential synthetic intermediate for caprazamycin B10 corresponding to the side-chain part (a precursor of the 5
western zone 4). For the β-hydroxyester moiety, a direct catalytic enantioselective thioamide-aldol reaction reported by this group was effective (6 and 7 to 8),11 whereas an enantioselective alcoholysis of 3-methylglutaric anhydride catalyzed by Ni2-(Schiff base) complex was newly developed to furnish the asymmetric diester component (12 to 13).12 Very recently, Takemoto and co-workers reported the first total synthesis of caprazamycin A,13 which employed a thiourea-catalyzed diastereoselective aldol reaction to connect the uridineand diazepanone parts, and Mitsunobu inversion for the cyclization to construct diazepanone system. The proper order of segment couplings was another key issue to avoid decomposition of the side chain moiety. Moreover, they pointed out that the array of fragile substructures within the skeleton required neutral conditions for final deprotection stage. As the continuation of our campaign described above, we aimed to complete the synthesis of caprazamycin B by condensation of the intermediates (4 and 5) and protecting group manipulation (Scheme 1).
6
Scheme 2. Unsuccessful segment couplings.
Having established the synthetic routes to (+)-caprazol and western zone, the remaining challenge for the synthesis of caprazamycin B was to assemble these intermediates and to remove the protecting groups. Preliminary investigation was unfruitful as shown in Scheme 2. A carboxylic acid 4 and protected caprazol 17 derived from one of the synthetic intermediates by a single operation was subjected to esterification conditions. Standard procedures, such as the EDCI method and Yamaguchi protocol, however, produced no targeted material 18 with recovered starting materials. 7
An acid chloride 19, prepared from 4 with Ghosez reagent under neutral conditions,14 treated with another possible intermediate 20 in the presence of DMAP, also afforded no desired protected caprazamycin B (21). In this case, the side product, presumably arising from β-elimination of β-acyloxy moiety within western zone, was obtained exclusively. The results described above highlight the unexpected difficulty in this seemingly simple acylation reaction. In addition, selective deprotection of the TBS group of 22 (an intermediate of our total synthesis of caprazol) to give 17 was not a trivial task in the presence of TIPS groups. Moreover, even if the selective desilylation and segment coupling had proceeded well, removal of the Boc and silyl groups, and acetals by acid-treatment was suspected to be incompatible with the acyl glycoside linkage of the side chain part, which is extremely vulnerable under the conditions. Accordingly, the strategy was changed to remove all of the protecting groups under neutral conditions, and to adopt a more reactive esterification protocol after careful screening of the conditions.
Scheme 3. Completion of the synthesis of caprazamycin B. Reagents and conditions: (a) CbzCl, NaHCO3, H2O, CH3CN, 0 °C to rt, 48 h, 79%; (b) BnOH, 8
BOP-Cl, Et3N, DMF, 0 °C to rt, 24 h, 63%; (c) Benzaldehyde dimethyl acetal, p-TsOH·H2O, DMF, rt, 72 h, 74%; (d) 4, MNBA, DMAP, Et3N, CH2Cl2, rt, 24 h, 32%; (e) Pd black, HCO2H, EtOH, rt, 6 h, 56%.
Scheme 3 shows the successful synthetic process. To replace all of the protecting groups to those removable upon hydrogenolysis, the synthesis commenced with (+)-caprazol 3, which can be obtained according to the previously reported procedure.8 The amino group was selectively masked by the Cbz group to give 23, followed by the formation of benzyl ester using BOP-Cl as the coupling reagent to afford 24. The subsequent conversion of a pair of vicinal diols to the corresponding benzylidene acetals 5 was achieved by standard methods. The segment-coupling in the next step was a formidable challenge, as observed in the model study described above. To this end, we first used acid chloride 19 with Et3N instead of DMAP in the previous model reaction, but only side products suffering from the β-elimination as observed in the model study were obtained. The desired condensation product 25 with the complete skeleton of caprazamycin B was afforded using Shiina’s protocol with MNBA and a catalytic amount of DMAP, 15 although the yield was rather moderate. Global deprotection of the final stage was unexpectedly troublesome. We first applied the conditions used in our total synthesis of (+)-caprazol 3 upon removal of the benzyl and carboxybenzyl groups; 5% Pd/C under atmospheric pressure of H2 at 50 ºC resulted in a mixture of a small amount of caprazamycin B (1) and decomposed products, from which the desired product could not be isolated 9
as a pure form. Transfer hydrogenation conditions using 5% Pd/C and 1,4-cyclohexadiene in MeOH or 2-propanol allowed for sequestration of the carboxybenzyl and benzyl groups, but both benzylidene acetals remained intact, even under reflux. Another surrogate of H2, HCO2NH4, resulted in the same reaction course. On the other hand, an additive acidic component, at as low a concentration as 0.5% of HCO2H in AcOEt,16 with the same palladium catalyst under atmospheric pressure of H2 afforded a complex mixture again. In this case, not only decomposition at some of the bond linkages alongside the molecular framework, but also reduction of the C-C double bond within uracil was observed. Eventually, we determined that conditions comprising Pd black in a mixture of EtOH and HCO2H (20:1) in the absence of H2 at room temperature reported by Takemoto and co-workers afforded caprazamycin B as the sole product. All the physicochemical data of the synthetic sample were fully identical to those obtained from the natural product. In summary, the synthesis of caprazamycin B was achieved from previously reported synthetic intermediates prepared using three catalytic asymmetric reactions developed by our group and one diastereoselective aldol-type reaction. The endgame process demonstrated herein addresses issues concerning the esterification of inert substrates and final deprotection of the unstable intermediate. With these established synthetic routes of (+)-caprazol and caprazamycin B, a SAR study to pursue promising leads for anti-XDR-TB agents and molecular probes, and further elucidation of the background of caprazamycin-related compounds, are underway.
10
Acknowledgments Acknowledg ments T.W. is grateful to the Takeda Science Foundation and The NOVARTIS Foundation (Japan) for the Promotion of Science for financial support. The authors thank Dr. Masayuki Igarashi for providing us a natural sample of caprazamycin B. The authors are thankful to Dr. Ryuichi Sawa, Ms. Yumiko Kubota, Ms. Kiyoko Iijima, and Ms. Yuko Takahashi (BIKAKEN) for the spectroscopic analysis.
Supplementary data Characterization of new data, and experimental procedures.
References and notes 1. (a) Igarashi, M.; Nakagawa, N.; Doi, N.; Hattori, S.; Naganawa, H.; Hamada, M. J. Antibiot. 2003, 56, 580. (b) Igarashi, M.; Takahashi, Y.; Shitara, T.; Nakamura, H.; Naganawa, H.; Miyake, T.; Akamatsu, Y. J. Antibiot. 2005, 58, 327. 2. Ishizaki, Y.; Hayashi, C.; Inoue, K.; Igarashi, M.; Takahashi, Y.; Pujari, V.; Crick, D. C.; Brennan, P. J.; Nomoto, A. J. Biol. Chem. 2013, 288, 30309. 3. Takahashi, Y.; Igarashi, M.; Miyake, T.; Soutome, H.; Ishikawa, K.; Komatsuki, Y.; Koyama, Y.; Nakagawa, N.; Hattori, S.; Inoue, K.; Doi, N.; Akamatsu, Y. J. Antibiot. 2013, 66, 171 4. Griffin, J. E.; Gawronski, J. D.; DeJesus, M. A.; Ioerger, T. R.; Akerley, B. J.; Sassetti, C. M. PLoS Pathog. 2011, 7, e1002251. 11
5. (a) Isono, K.; Uramoto, M.; Kusakabe, H.; Kimura, K. I.; Izaki, K.; Nelson, C. C.; McCloskey, J. A. J. Antibiot. 1985, 38, 1617. (b) Ubukata, M.; Kimura, K.; Isono, K.; Nelson, C. C.; Gregson, J. M.; McCloskey, J. A. J. Org. Chem. 1992, 57, 6392. (c) Fujita, Y.; Kizuka, M.; Funabashi, M.; Ogawa, Y.; Ishikawa, T.; Nonaka, K.; Takatsu, T. J. Antibiot. 2011, 64, 495. 6. (a) Fukunishi, S.; Ubukata, M.; Nakajima, N. Heterocycles 2005, 66, 129. (b) Fukunishi, S.; Ubukata, M.; Nakajima, N. Heterocycles 2007, 73, 627. (c) Drouillat, B.; Poupardin, O.; Bourdreux, Y.; Greck, C. Tetrahedron Lett. 2003, 44, 2781. (d) Drouillat, B.; Bourdreux, Y.; Perdon, D.; Greek, C. Tetrahedron: Asymmetry 2007, 18, 1955. (e) Kim, K. S.; Cho, I. H.; Ahn, Y. H.; Ilpark, J. J. Chem. Soc. Perkin Trans. 1 1995, 1783. (f) Kim, K. S.; Ahn, Y. H. Tetrahedron: Asymmetry 1998, 9, 3601. (g) Gravier-Pelletier, C.; Charvet, I.; LeMerrer, Y.; Depezay, J. C. J. Carbohydr. Chem. 1997, 16, 129. (h) Le Merrer, Y.; Gravier-Pelletier, C.; Gerrouache, M.; Depezay, J. C. Tetrahedron Lett. 1998, 39, 385. (i) Gravier-Pelletier, C.; Milla, M.; Le Merrer, Y.; Depezay, J. C. Eur. J. Org. Chem. 2001, 3089. (j) Monasson, O.; Ginisty, M.; Bertho, G.; Gravier-Pelletier, C.; Le Merrer, Y. Tetrahedron Lett. 2007, 48, 8149. (k) Monasson, O.; Ginisty, M.; Mravljak, J.; Bertho, G.; Gravier-Pelletier, C.; Le Merrer, Y. Tetrahedron: Asymmetry 2009, 20, 2320. (l) Sarabia, F.; Martin-Ortiz, L.; Lopez-Herrera, F. J. Org. Lett. 2003, 5, 3927. (m) Sarabia, F.; Vivar-Garcia, C.; Garcia-Ruiz, C.; Martin-Ortiz, L.; Romero-Carrasco, A. J. Org. Chem. 2012, 77, 1328. (n) Spork, A. P.; Koppermann, S.; Dittrich, B.; Herbst-Irmer, R.; Ducho, C. Tetrahedron: Asymmetry 2010, 21, 763. (o) Miyaoka, H.; Wada, J.; Kawashima, E. Heterocycles 12
2014, 88, 719. 7. (a) Hirano, S.; Ichikawa, S.; Matsuda, A. Angew. Chem. Int. Ed. 2005, 44, 1854. (b) Hirano, S.; Ichikawa, S.; Matsuda, A. J. Org. Chem. 2007, 72, 9936. 8. Gopinath, P., Wang, L., Abe, H., Ravi, G., Masuda, T., Watanabe, T., Shibasaki, M. Org. Lett., 2014, 16, 3364-3367. 9. (a) Nitabaru, T.; Kumagai, N.; Shibasaki, M. Tetrahedron Lett. 2008, 49, 272. (b) Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 13860. (c) Nitabaru, T.; Kumagai, N.; Shibasaki, M. Angew. Chem. Int. Ed. 2012, 51, 1644. 10. Gopinath, P.; Watanabe, T.; Shibasaki, M. J. Org. Chem. 2012, 77, 9260. 11. (a) Iwata, M.; Yazaki, R.; Suzuki, Y.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 18244. (b) Iwata, M.; Yazaki, R.; Chen, I. H.; Sureshkumar, D.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2011, 133, 5554. (c) Kawato, Y.; Iwata, M.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Tetrahedron 2011, 67, 6539. 12. (a) Gopinath, P.; Watanabe, T.; Shibasaki, M. Org. Lett. 2012, 14, 1358. (b) Matsunaga, S.; Shibasaki, M. Synthesis 2013, 45, 421. 13. Nakamura, H.; Tsukano, C.; Yasui, M.; Yokouchi, S.; Igarashi, M.; Takemoto, Y. Angew. Chem. Int. Ed. 2015, 54, 3136. 14. (a) Haveaux, B.; Dekoker, A.; Rens, M.; Sidani, A. R.; Toye, J.; Ghosez, L. Org. Synth. 1980, 59, 26. (b) Fürstner, A.; Konetzki, I. J. Org. Chem. 1998, 63, 3072. 13
15. Shiina, I.; Kubota, M., Oshiumi, H.; Hashizume, M. J. Org. Chem. 2004, 69, 1822. 16. Aleiwi, B. A.; Kurosu, M. Tetrahedron Lett. 2012, 53, 3758. Legends
Figure 1. Caprazamycin B and related compounds.
Scheme 1. Synthetic strategy of caprazamycin B.
Scheme 2. Unsuccessful segment couplings.
Scheme 3. Completion of the synthesis of caprazamycin B. Reagents and conditions: (a) CbzCl, NaHCO3, H2O, CH3CN, 0 °C to rt, 48 h, 79%; (b) BnOH, BOP-Cl, Et3N, DMF, 0 °C to rt, 24 h, 63%; (c) Benzaldehyde dimethyl acetal, p-TsOH·H2O, DMF, rt, 72 h, 74%; (d) 4, MNBA, DMAP, Et3N, CH2Cl2, rt, 24 h, 32%; (e) Pd black, HCO2H, EtOH, rt, 6 h, 56%.
14
S0040-4039(15)00702-9 http://dx.doi.org/10.1016/j.tetlet.2015.04.065 TETL 46204
To appear in:
Tetrahedron Letters
Received Date: Revised Date: Accepted Date:
16 March 2015 10 April 2015 17 April 2015
Please cite this article as: Abe, H., Gopinath, P., Ravi, G., Wang, L., Watanabe, T., Shibasaki, M., Synthesis of Caprazamycin B, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.04.065
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Synthesis of Caprazamycin B
Hikaru Abe, Purushothaman Gopinath, Gandamala Ravi, Lu Wang, Takumi Watanabe*, Masakatsu Shibasaki*
Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
ABSTRACT: Caprazamycin B was successfully synthesized via caprazol. In the present synthesis, the choices of the segment coupling conditions and protecting groups were unexpectedly narrow. Only Shiina’s protocol provided the ester linkage between the unreactive secondary hydroxyl group on the diazepanone ring system and the side chain moiety (western zone). Upon final global deprotection, hydrogenolysis conditions were compatible with substructures that are unstable under acidic and basic environments.
1
(Graphical Abstract)
Keywords: Caprazamycin B; Liponucleoside-antibiotic; Natural product synthesis; Anti-tuberculosis agent
* Corresponding authors, tel.: +81 3 3441 4173; fax: +81 3 3441 7589 (T.W.); tel.: +81 3 3447 7779; fax:
+81
3
3441
7589
(M.S.);
addresses:
[email protected] (M.S.).
2
[email protected]
(T.W.),
Caprazamycins, lipo-nucleoside antibiotics that comprise a mixture of seven constituents possessing aliphatic side chains of varying lengths and branched patterns (Figure 1), are considered as promising anti-tuberculosis (TB) natural products.1 Among them, caprazamycin B (1) exerts the most potent anti-TB activity, due mainly to the inhibition of MraY,2 a key enzyme in the peptidoglycan biosynthesis pathway of the pathogens. Subsequent semisynthetic structure-activity relationship (SAR) studies were performed using caprazamycins as starting materials to develop CPZEN-45 (2),3 an anti-XDR-TB (extensively multidrug-resistant TB) agent; XDR-TB is a TB strain that is resistant to many of the currently available clinical drugs. Notably, the mechanisms underlying the anti-XDR-TB activity of CPZEN-45 is the inhibition of WecA.2 This enzyme is involved in the biosynthesis of mycolyl arabinogalactan, which is essential for Mycobacterium tuberculosis,4 yet it has never been a molecular target of clinical anti-TB drugs. Consequently, synthetic chemical libraries in which caprazamycin derivatives are reposited are potential sources of lead compounds for urgently demanded anti-XDR-TB agents. Thereby, efficient synthetic routes to caprazamycins and related natural products5 that would enable access to their derivatives with rich structural diversity have been extensively pursued.
3
Figure 1. Caprazamycin B and related compounds.
Caprazamycins have attracted interest from the synthetic community not only for their unique biological activities, but also due to their complex molecular architecture: 19 stereogenic centers are densely furnished on the uncommon framework, including the central diazepanone moiety, and substructures susceptible to both acidic (acylglycoside linkage) and basic (β-amino-α-hydroxycarbonyl moieties) conditions are present. Indeed, tremendous effort by many research groups has been dedicated to the synthesis of caprazamycin-related natural products,6 and two total syntheses of (+)-caprazol have been disclosed to date.7,8 (+)-Caprazol (3, Figure 1) was discovered in the isolation process of caprazamycins from natural resources, and is regarded as the core structure of caprazamycins. The first total synthesis of this molecule was reported by Matsuda, Ichikawa and co-workers in 2005.7 The synthesis tactically took advantage of the Sharpless’ catalytic asymmetric aminohydroxylation and the pre-organized stereochemistry of D-serine to build the syn-β-amino-α-hydroxyamide portion at the juncture of the diazepanone and the uridine cores, and the anti-congener embedded in the diazepanone ring, 4
respectively.
Scheme 1. Synthetic strategy of caprazamycin B.
We recently completed a catalytic asymmetric total synthesis of (+)-caprazol as a part of synthetic endeavor toward caprazamycin B.8 Our approach centered on catalytic enantioselective and diastereoselective aldol-type chemistries to provide the stereo-elements required to synthesize caprazol and caprazamycin B (Scheme 1). The syn- and anti-β-amino-α-hydroxyamide substructures depicted above were constructed by a catalytic isocyanoacetate-aldol reaction (14 and 15 to 16), and an anti-selective catalytic asymmetric nitroaldol reaction developed in our laboratory (9 and 10 to 11),9 respectively. This strategy could be used to efficiently build the molecular skeleton with simultaneous installation of the correct configuration with highly stereoselective C-C bond forming reactions. In advance to the report, we also reported the catalytic asymmetric synthesis of a potential synthetic intermediate for caprazamycin B10 corresponding to the side-chain part (a precursor of the 5
western zone 4). For the β-hydroxyester moiety, a direct catalytic enantioselective thioamide-aldol reaction reported by this group was effective (6 and 7 to 8),11 whereas an enantioselective alcoholysis of 3-methylglutaric anhydride catalyzed by Ni2-(Schiff base) complex was newly developed to furnish the asymmetric diester component (12 to 13).12 Very recently, Takemoto and co-workers reported the first total synthesis of caprazamycin A,13 which employed a thiourea-catalyzed diastereoselective aldol reaction to connect the uridineand diazepanone parts, and Mitsunobu inversion for the cyclization to construct diazepanone system. The proper order of segment couplings was another key issue to avoid decomposition of the side chain moiety. Moreover, they pointed out that the array of fragile substructures within the skeleton required neutral conditions for final deprotection stage. As the continuation of our campaign described above, we aimed to complete the synthesis of caprazamycin B by condensation of the intermediates (4 and 5) and protecting group manipulation (Scheme 1).
6
Scheme 2. Unsuccessful segment couplings.
Having established the synthetic routes to (+)-caprazol and western zone, the remaining challenge for the synthesis of caprazamycin B was to assemble these intermediates and to remove the protecting groups. Preliminary investigation was unfruitful as shown in Scheme 2. A carboxylic acid 4 and protected caprazol 17 derived from one of the synthetic intermediates by a single operation was subjected to esterification conditions. Standard procedures, such as the EDCI method and Yamaguchi protocol, however, produced no targeted material 18 with recovered starting materials. 7
An acid chloride 19, prepared from 4 with Ghosez reagent under neutral conditions,14 treated with another possible intermediate 20 in the presence of DMAP, also afforded no desired protected caprazamycin B (21). In this case, the side product, presumably arising from β-elimination of β-acyloxy moiety within western zone, was obtained exclusively. The results described above highlight the unexpected difficulty in this seemingly simple acylation reaction. In addition, selective deprotection of the TBS group of 22 (an intermediate of our total synthesis of caprazol) to give 17 was not a trivial task in the presence of TIPS groups. Moreover, even if the selective desilylation and segment coupling had proceeded well, removal of the Boc and silyl groups, and acetals by acid-treatment was suspected to be incompatible with the acyl glycoside linkage of the side chain part, which is extremely vulnerable under the conditions. Accordingly, the strategy was changed to remove all of the protecting groups under neutral conditions, and to adopt a more reactive esterification protocol after careful screening of the conditions.
Scheme 3. Completion of the synthesis of caprazamycin B. Reagents and conditions: (a) CbzCl, NaHCO3, H2O, CH3CN, 0 °C to rt, 48 h, 79%; (b) BnOH, 8
BOP-Cl, Et3N, DMF, 0 °C to rt, 24 h, 63%; (c) Benzaldehyde dimethyl acetal, p-TsOH·H2O, DMF, rt, 72 h, 74%; (d) 4, MNBA, DMAP, Et3N, CH2Cl2, rt, 24 h, 32%; (e) Pd black, HCO2H, EtOH, rt, 6 h, 56%.
Scheme 3 shows the successful synthetic process. To replace all of the protecting groups to those removable upon hydrogenolysis, the synthesis commenced with (+)-caprazol 3, which can be obtained according to the previously reported procedure.8 The amino group was selectively masked by the Cbz group to give 23, followed by the formation of benzyl ester using BOP-Cl as the coupling reagent to afford 24. The subsequent conversion of a pair of vicinal diols to the corresponding benzylidene acetals 5 was achieved by standard methods. The segment-coupling in the next step was a formidable challenge, as observed in the model study described above. To this end, we first used acid chloride 19 with Et3N instead of DMAP in the previous model reaction, but only side products suffering from the β-elimination as observed in the model study were obtained. The desired condensation product 25 with the complete skeleton of caprazamycin B was afforded using Shiina’s protocol with MNBA and a catalytic amount of DMAP, 15 although the yield was rather moderate. Global deprotection of the final stage was unexpectedly troublesome. We first applied the conditions used in our total synthesis of (+)-caprazol 3 upon removal of the benzyl and carboxybenzyl groups; 5% Pd/C under atmospheric pressure of H2 at 50 ºC resulted in a mixture of a small amount of caprazamycin B (1) and decomposed products, from which the desired product could not be isolated 9
as a pure form. Transfer hydrogenation conditions using 5% Pd/C and 1,4-cyclohexadiene in MeOH or 2-propanol allowed for sequestration of the carboxybenzyl and benzyl groups, but both benzylidene acetals remained intact, even under reflux. Another surrogate of H2, HCO2NH4, resulted in the same reaction course. On the other hand, an additive acidic component, at as low a concentration as 0.5% of HCO2H in AcOEt,16 with the same palladium catalyst under atmospheric pressure of H2 afforded a complex mixture again. In this case, not only decomposition at some of the bond linkages alongside the molecular framework, but also reduction of the C-C double bond within uracil was observed. Eventually, we determined that conditions comprising Pd black in a mixture of EtOH and HCO2H (20:1) in the absence of H2 at room temperature reported by Takemoto and co-workers afforded caprazamycin B as the sole product. All the physicochemical data of the synthetic sample were fully identical to those obtained from the natural product. In summary, the synthesis of caprazamycin B was achieved from previously reported synthetic intermediates prepared using three catalytic asymmetric reactions developed by our group and one diastereoselective aldol-type reaction. The endgame process demonstrated herein addresses issues concerning the esterification of inert substrates and final deprotection of the unstable intermediate. With these established synthetic routes of (+)-caprazol and caprazamycin B, a SAR study to pursue promising leads for anti-XDR-TB agents and molecular probes, and further elucidation of the background of caprazamycin-related compounds, are underway.
10
Acknowledgments Acknowledg ments T.W. is grateful to the Takeda Science Foundation and The NOVARTIS Foundation (Japan) for the Promotion of Science for financial support. The authors thank Dr. Masayuki Igarashi for providing us a natural sample of caprazamycin B. The authors are thankful to Dr. Ryuichi Sawa, Ms. Yumiko Kubota, Ms. Kiyoko Iijima, and Ms. Yuko Takahashi (BIKAKEN) for the spectroscopic analysis.
Supplementary data Characterization of new data, and experimental procedures.
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15. Shiina, I.; Kubota, M., Oshiumi, H.; Hashizume, M. J. Org. Chem. 2004, 69, 1822. 16. Aleiwi, B. A.; Kurosu, M. Tetrahedron Lett. 2012, 53, 3758. Legends
Figure 1. Caprazamycin B and related compounds.
Scheme 1. Synthetic strategy of caprazamycin B.
Scheme 2. Unsuccessful segment couplings.
Scheme 3. Completion of the synthesis of caprazamycin B. Reagents and conditions: (a) CbzCl, NaHCO3, H2O, CH3CN, 0 °C to rt, 48 h, 79%; (b) BnOH, BOP-Cl, Et3N, DMF, 0 °C to rt, 24 h, 63%; (c) Benzaldehyde dimethyl acetal, p-TsOH·H2O, DMF, rt, 72 h, 74%; (d) 4, MNBA, DMAP, Et3N, CH2Cl2, rt, 24 h, 32%; (e) Pd black, HCO2H, EtOH, rt, 6 h, 56%.
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