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Review of the Reported Methods
The unprecedented framework makes chaetominine an idea target for exploring novel synthetic strategies. Many research groups have explored on the total synthesis of chaetominine.8
Snider’s synthesis of chaetominine
In 2007, Snider group8a reported the first total synthesis of chaetominine (Scheme 2.1). Starting from iodocarbamate 2.10, a Buchwald Pd(0)-catalyzed cyclization afforded tricycle 2.11. Then, epoxidation with oxaziridine 2.12 followed by NaBH4 reduction led to hydroxy imidazolidinone 2.13. TES protection and catalytic hydrogenolysis of Cbz protecting group of compound 2.13 afforded the amino ester 2.15. Lactamization of 2.15 in the presence of DMAP provided the key compound 2.16 which contained the skeleton of chaetaminine. Troc deprotection followed by construction of quinazolinone ring and removal of the TES group completed the first asymmetric total synthesis of chaetominine (2.1) in 10 steps, 6.2% overall yield.
Evano’s synthesis of chaetominine
In 2008, Evano’s group8b reported a total synthesis of ()-chaetominine (2.1) (Scheme 2.2), starting from the D-tryptophan. The synthesis of dipeptide compound 2.21 was achieved through two intermolecular amide coupling reactions. Protection of the indole nitrogen with a Cbz group afforded 2.22, which was treated with Hg(OTA)2 and I2 to afford compound 2.23. Copper catalyzed intramolecular amination afforded compound 2.24 without epimerization. Deprotection of Cbz group, followed by DMDO epoxidation at85 °C gave an extremely unstable epoxy intermediate 2.25, which directly rearranges to the hydroxyl imine 2.26. Due to the steric effect between Phth protecting group and DMDO, the epoxidation took place with a high diastereoslectivity (de>95%). Reduction of the hydroxyl imine 2.26 with NaBH3CN provided an unstable compound 2.27, which was transformed into compound 2.28 during silica gel purification. The subsequent steps are similar to the method of Snider (Scheme 2.1). This total synthesis of chaetominine was achieved in 10% overall yield over 14 steps.
In 2009, Evano’s group8e reported an improved synthesis of 2.26 from 2.21 employing singlet oxygen oxidation (Scheme 2.3).
Papeo’s synthesis of chaetominine
In 2009, Papeo’s group8d reported a novel method for the synthesis of chaetominine (Scheme 2.4). In this work, the quinazoline ring was constructed at an early stage to reduce the steps of protection and deprotection. Specifically, the commercial available D-tryptophan methyl ester was condensed with anthranilic acid followed by reaction with ethyl formate in the presence of TsOH to give quinazolinone 2.29. The methyl ester was then hydrolyzed and coupled with alanine tert-butyl ester hydrochloride to afford di-peptide 2.30. Oxidative cyclization in the presence of NCS and Et3N at78 °C led to 2.31, which was converted to 2.33 through removal of the tert-butyl group of the ester followed by intramolecular amide formation. Oxidation the indole moiety with 2.34 afforded deoxygenated compound 2.35. Reductive removal of the methoxyl group afforded the natural product chaetominine in 9.3% overall yield over nine steps.
Huang group’s synthesis of chaetominine
In 2009, Huang group developed its first strategy for the total synthesis of chaetominine (Scheme 2.5).8c,8f This short synthesis has high redox economy which is protecting group-free. First, D-tryptophan was reacted with 2-nitrobenzoyl chloride to form compound 2.36 through amide condensation reaction. The carboxyl group was then activated with isobutyl chloroformate and reacted with L-alanine methyl ester hydrochloride at low temperature to afford the dipeptide 2.37. Subsequently, Following the method developed by Shi’s group,9 compound 2.37 was reacted with HC(OEt)3 in the presence of Zn/TiCl4 to afford the quinazolinone derivative 2.38. Epoxidation with DMDO followed by biscyclization in DMSO (which have been treated with CaH2) afforded ()-chaetominine (2.1) in 42% yield, along with monocyclized compound 2.41 in 3% yield and 2.42 in 51% yield. The compound 2.42 was cyclized by treating with CH3ONa to provide (+)-11-epi-chaetominine (2.43) in 90% yield.
Soon after, Huang’s group developed the second generation total synthesis of ()-chaetominine (Scheme 2.6).8g The synthesis of ()-chaetominine (2.1) and ()-11-epi-chaetominine (2.47) was achieved in 23.2% yield and 31.6% yield, respectively, starting from L-tryptophan.For the synthesis of compound 2.46, a similar previously reported route was adopted. The compound 2.46 was refluxed in toluene for 3 days in the presence of a catalytic amount of DMAP to furnish ()-chaetominine by selective epimerization. Compound 2.46 can also be bis-epimerized in the presence of CH3ONa under low temperature to give ()-11-epi-chaetominine in 82% yield.
These results suggested that the biosynthetic pathway of chaetominine may start from L-tryptophan.
Xia’s synthesis of (+)-11-epi-chaetominine
Xia’s group reported the synthesis of (+)-11-epi-chaetominine by employing a route similar to the Huang synthesis.8i They prepared the compound 2.29 by following papeo’s method. The methyl ester 2.29 was converted to dipipetide 2.39 through ester hydrolysis and amide formation. The key copper-catalyzed radical cyclization of 2.39 afforded compound 2.48, which was converted to (+)-11-epi-chaetominine (2.43) in 93% yield by treating with Zn/ AcOH. Total synthesis of (+)-11-epi-chaetominine (2.43) was completed in 48% overall yield over 6 steps.
Roche’s synthesis of 2-fluoro-chaetominine
Roche and Tréguier used a 1:1 epimeric mixture of N-Phth-Trp-Phe-OC6F5 (2.49) in their synthesis of 2-fluoro-chaetominine due to the ease of epimerization of compound 2.49 during the synthesis.8j Then Selectfluor-triggered double cyclization cascade reaction with compound 2.49 afforded the tetracyclic core 2.50 as a mixture of four diastereomers in a ratio of 2:1:1:4 (combined yield: 42%), from which the overall C3-C14 cis/trans ratio was 5:3 (Scheme 2.8).
Although four research groups have completed the synthesis of chaetominine (Scheme 2.9), but the synthesis of other members of chaetominine-type alkaloids have not been reported, especially ()- isochaetominines A–C (2.4–2.6), which feature a unique all-cis-stereochemistry that is different from chaetominine.
Research Plan
The proposed retrosynthetic analysis of isochaetominine A–C (2.4–2.6) was shown in Scheme 2.10. Previous results gained from the synthesis of ()-chaetominine (2.1)8c,f-h revealed that only when the anti-dispose of hydroxyl group at C-3 and the quinazolinonyl group at C-14 in compound 2.51 can the final lactamization occur spontaneously. In addition, the stereocenter at C-14 is prone to epimerization.
Hence, the key issue in this project is the epimerization- free approach to the all-cis-stereochemistry existed in ()-pseudofischerine (2.2), ()-isochaetominines AC (2.4–2.6) and isochaetominine (2.9).
First of all, we choose isochaetominine A–C (2.4–2.6) as our first targets. The imidazolinone ring of 2.4–2.6 could be formed from the corresponding carboxylic acid under mild lactamization conditions using a racemization- free method.10,11 Thus benzyl valinate was choosed as an amino acid component to avoid emimerization during ester to acid conversion. Non-diastereoselective epoxidation of quinazolinonyl dipeptide 2.52 would yield two diastereomeric expoxides (no shown) and one of them is expected to convert spontaneously to the proposed structure of aniquinazoline D (2.3) when R is the isopropyl group, the other expoxide will form the monocyclization product 2.51, which is an ideal precursor for isochaetominines C (2.6). The dipeptide 2.52 could be prepared from D-Trp with L-benzyl valinate through 3 steps.
We also plan to use the stereodivergent strategy for the synthesis of all other members of chaetominine-type alkaloids. Through the combination of D or L-tryptophan and different benzyl valinate or alaninate, a similar route may be employed for the synthesis of all eight 2,3-cis-stereoisomers of ()- isochaetominine C and isochaetominine (Figure 2.2).
Table of contents :
Chapter 1 General Introduction
Chapter 2 Stereodivergent and enantioselective total syntheses of chaetominine-type alkaloids
2.1 Review of the Reported Methods
2.2 Research Plan
2.3 Results and Discussion
2.4 Conclusion
2.5 Experimental Section
References
Chapter 3 Azaphilic Radical Cascade Cyclization for the Synthesis of Imidazo-Fused Heteroaromatics
3.1 Review of the Reported Methods
3.2 Research Plan
3.3 Results and Discussion
3.4 Reaction in aqueous solution
3.4 Conclusion
3.5 Experimental Section
References
Chapter 4 Toward Analogs of the 2-Carboxyl-6-HydroxyOctahydro- Indole (CHOI) Unit
4.1 Review of the Reported Methods
4.2 Research Plan
4.3 Results and Discussion
4.4 Conclusion
4.5 Experimental Section
References
Chapter 5 General Conclusion
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