Synthesis of 1,1’-Dideaza-Quinine: A Proof of Concept · Once a successful reaction is determined...
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Synthesis of 1,1’-Dideaza-Quinine: A Proof of Concept Jackson Eber, Adam Montoya,* David E. Minter* Department of Chemistry and Biochemistry, Texas Christian University, Fort Worth, TX 76129 Model System Experimentation Figure 1. Structures of title compounds Model System Complications Model System Ongoing Experimentation Conclusions Abstract Quinine is a naturally occurring alkaloid found in the bark of the cinchona tree. Its medicinal relevance cannot be overstated as it is one of the most widely used anti-malarial drugs in the world. While the synthetic pathway to derive quinine is of limited relevance due to its abundance and ease of extraction, the puzzle of engineering reactions to isolate a stereochemically pure product of quinine captivated chemists for generations. The purpose of this study was to prove the conceptual route proposed by Stotter, Friedman, and Minter 1 for the stereochemically pure total synthesis of quinine via a non-nitrogenous analog where the two nitrogen atoms of quinine are substituted with carbon atoms. The product of the analogous route is 1,1’-Dideaza-Quinine. Quinine is stereochemically complex, containing four separate stereocenters, thus the synthesis of quinine opens up the possibility of generating sixteen different isomeric structures. While the total synthesis of quinine with the correct stereochemistry was accomplished in 2001, 2 the proposed route simplifies the process by relying on a stereospecific aldol addition to eliminate potential isomerization. 1 The results of the study are not yet conclusive for the validation of the proposed conceptual route. Future experimentation will occur in order generate the necessary substrate to perform the stereoselective aldol addition reaction. Additionally, due to the analogous nature of the synthetic route utilized, two novel compounds were generated adding to the body of knowledge available to the Chemistry community. Figure 2. Model System Progress Once a successful reaction is determined for the conversion of the nitrile to the aldehyde (Compound X), it will be reacted with the ketone (Compound Y), which has already been obtained, in basic solution to result in an aldol addition reaction which will combine both substrates. The product of the reaction has an acidic hydrogen located adjacent to the carbonyl resulting in an epimerizable center and loss of stereochemical control. This issue is alleviated by the quick conversion to the alcohol without isolation of the ketone intermediate in order to remove the epimerizable center. Subsequent reduction of the alcohol will lead to the generation of the target molecule, 1,1’Dideaza-Quinine. Figure 3. Model System Complications Acknowledgments To Dr. Minter for his guidance on this project and for his support throughout my undergraduate experience at TCU from four years of advising and drop-in conversations. To Adam Montoya for his significant assistance in developing my research techniques and for making the many hours of lab research more enjoyable and encouraging. Lastly, to TCU for the facilities and funding that made this research possible. Figure 5. Stereoselective aldol addition reaction for the subsequent reduction to yield 1,1’-Dideaza-Quinine All reactions were performed on a model system that differed from the target molecule, Quinine, in that the nitrogen atoms of Quinine were substituted with carbons, thereby making the target molecule 1,1’-Dideaza- Quinine. This model system has much more readily available substrates of higher complexity leading to a simpler synthesis of the target molecule which would facilitate the proof of concept much quicker. Future plans for this project include determining a reaction that converts the nitrile to the aldehyde which has not been accomplished as indicated by the crossed out arrow shown above. Yields are reported for all successful transformations. Once proof of concept is determined, experimentation will be done to optimize the yields involved in this pathway. The aromatic aldehyde, listed as Compound X in Figure 5, has proven to be extremely difficult to produce from the aromatic nitrile precursor, indicated in Figure 3. Without having the aldehyde of interest, the reaction schematic proposed in Figure 5 cannot be carried out. Thus, until the aldehyde, Compound X, is generated, the proof of concept for the stereoselective synthesis of 1,1’-Dideaza-Quinine cannot be completed. Therefore, ongoing and future experimentation will be directed toward finding a viable reaction for the production of the aldehyde and then carrying out the scheme shown in Figure 5. Additionally, along the schematic pathway for the generation of the ketone in Figure 5, Compound Y, two novel compounds were isolated. These two compounds, indicated by an asterisk in Figure 2, will be published and added to the literature of known compounds following combustion analysis and X-ray crystallography. Model System Future Experimentation Figure 4. Conversion of nitrile to aldehyde with formic acid and platinum catalyst Our attempts at the conversion of the nitrile to the aldehyde shown above have not yet been successful. The generation of the aldehyde is vital to the synthesis of 1,1’-Dideaza-Quinine because it is one of the two components necessary for the aldol addition reaction shown in Figure 5. As such, a variety of different methods have been employed to produce this molecule, however, none have worked thus far. The most promising route determined experimentally is to first convert the nitrile into a carboxylic acid, then generate the Weinreb amide, and lastly reduce the amide with a hydride source to be left with the aldehyde, as indicated in the last reaction scheme above. Producing the Weinreb amide has also proven difficult, but the reaction will be performed again to ensure this pathway is invalid. Additionally, conversion of the nitrile to the aldehyde is currently being attempted, as shown in Figure 4, using formic acid and a platinum catalyst. While platinum is not cost effective, its efficacy is still worth exploring as most other common nitrile to aldehyde conversions have been attempted. OCH 3 H OH H N N OCH 3 H OH H Quinine 1,1'-Dideaza-Quinine + O OCH 3 H 3 CO O HO O I O O O O O OH OH HO O AlCl 3 O H 3 CO H 3 CO CN H 3 CO CN H 3 CO O ≡ catalyst 1. KOH in (CH 2 OH) 2 2. HCl 1. K 2 CO 3 / KI in EtOAc 2. I 2 98% 63% 83% 1. Sn(Bu) 3 H in C 6 H 6 2. 10% KF 60% 37% 91% 83% DIBAL PCC 1. (Ph) 3 P=CH 2 2. H + 80% 91% 1. TMSCN 2. BF 3 etherate (cat.) chloranil 1,4-dioxane Overall Yield = 8.6% OCH 3 CN OCH 3 PtO 2 60 o C; 7 hr 80% formic acid O X 40% KOH EtOH H 3 CO CN H 3 CO O HO H 3 CO H N O EDC-HCl; HOBt O N O LiAlH 4 H 3 CO O 82% X OCH 3 O OCH 3 O + OH H OCH 3 HO OH H OCH 3 OH H H H H - O enolate [OH - ] [R] X Y O * * References (1) Stotter, P. L.; Friedman, M. D.; Minter, D. E. J. Org. Chem. 1985, 50 (1), 29–31. (2) Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Balkovec, J. M.; Tata, J. R.; Dake, G. R. Journal of the American Chemical Society 2001, 123 (35), 3239–3242.
Transcript of Synthesis of 1,1’-Dideaza-Quinine: A Proof of Concept · Once a successful reaction is determined...
Synthesis of 1,1’-Dideaza-Quinine: A Proof of ConceptJackson Eber, Adam Montoya,* David E. Minter*
Department of Chemistry and Biochemistry, Texas Christian University, Fort Worth, TX 76129
Model System Experimentation
Figure 1. Structures of title compounds
Model System Complications
Model System Ongoing Experimentation
Conclusions
Abstract
Quinine is a naturally occurring alkaloid found in the bark ofthe cinchona tree. Its medicinal relevance cannot beoverstated as it is one of the most widely used anti-malarialdrugs in the world. While the synthetic pathway to derivequinine is of limited relevance due to its abundance and easeof extraction, the puzzle of engineering reactions to isolate astereochemically pure product of quinine captivatedchemists for generations. The purpose of this study was toprove the conceptual route proposed by Stotter, Friedman,and Minter1 for the stereochemically pure total synthesis ofquinine via a non-nitrogenous analog where the two nitrogenatoms of quinine are substituted with carbon atoms. Theproduct of the analogous route is 1,1’-Dideaza-Quinine.Quinine is stereochemically complex, containing fourseparate stereocenters, thus the synthesis of quinine opensup the possibility of generating sixteen different isomericstructures. While the total synthesis of quinine with thecorrect stereochemistry was accomplished in 2001,2 theproposed route simplifies the process by relying on astereospecific aldol addition to eliminate potentialisomerization.1 The results of the study are not yetconclusive for the validation of the proposed conceptualroute. Future experimentation will occur in order generatethe necessary substrate to perform the stereoselective aldoladdition reaction. Additionally, due to the analogous natureof the synthetic route utilized, two novel compounds weregenerated adding to the body of knowledge available to theChemistry community.
Figure 2. Model System Progress
Once a successful reaction is determined for the conversion of the nitrile to the aldehyde (Compound X), it willbe reacted with the ketone (Compound Y), which has already been obtained, in basic solution to result in analdol addition reaction which will combine both substrates. The product of the reaction has an acidic hydrogenlocated adjacent to the carbonyl resulting in an epimerizable center and loss of stereochemical control. Thisissue is alleviated by the quick conversion to the alcohol without isolation of the ketone intermediate in order toremove the epimerizable center. Subsequent reduction of the alcohol will lead to the generation of the targetmolecule, 1,1’Dideaza-Quinine.
Figure 3. Model System Complications
AcknowledgmentsTo Dr. Minter for his guidance on this project and for his support throughout my undergraduate experience at TCU from fouryears of advising and drop-in conversations. To Adam Montoya for his significant assistance in developing my researchtechniques and for making the many hours of lab research more enjoyable and encouraging. Lastly, to TCU for the facilitiesand funding that made this research possible.
Figure 5. Stereoselective aldol addition reaction for the subsequent reduction to yield 1,1’-Dideaza-Quinine
All reactions were performed on a model system that differed from the target molecule, Quinine, in that thenitrogen atoms of Quinine were substituted with carbons, thereby making the target molecule 1,1’-Dideaza-Quinine. This model system has much more readily available substrates of higher complexity leading to asimpler synthesis of the target molecule which would facilitate the proof of concept much quicker. Future plansfor this project include determining a reaction that converts the nitrile to the aldehyde which has not beenaccomplished as indicated by the crossed out arrow shown above. Yields are reported for all successfultransformations. Once proof of concept is determined, experimentation will be done to optimize the yieldsinvolved in this pathway.
The aromatic aldehyde, listed as Compound X in Figure 5, has proven to be extremely difficult to produce from the aromaticnitrile precursor, indicated in Figure 3. Without having the aldehyde of interest, the reaction schematic proposed in Figure 5cannot be carried out. Thus, until the aldehyde, Compound X, is generated, the proof of concept for the stereoselectivesynthesis of 1,1’-Dideaza-Quinine cannot be completed. Therefore, ongoing and future experimentation will be directedtoward finding a viable reaction for the production of the aldehyde and then carrying out the scheme shown in Figure 5.Additionally, along the schematic pathway for the generation of the ketone in Figure 5, Compound Y, two novel compoundswere isolated. These two compounds, indicated by an asterisk in Figure 2, will be published and added to the literature ofknown compounds following combustion analysis and X-ray crystallography.
Model System Future Experimentation
Figure 4. Conversion of nitrile to aldehyde with formic acid and platinum catalyst
Our attempts at the conversion of the nitrile to the aldehyde shown above have not yet been successful. The generation ofthe aldehyde is vital to the synthesis of 1,1’-Dideaza-Quinine because it is one of the two components necessary for thealdol addition reaction shown in Figure 5. As such, a variety of different methods have been employed to produce thismolecule, however, none have worked thus far. The most promising route determined experimentally is to first convert thenitrile into a carboxylic acid, then generate the Weinreb amide, and lastly reduce the amide with a hydride source to be leftwith the aldehyde, as indicated in the last reaction scheme above. Producing the Weinreb amide has also proven difficult, butthe reaction will be performed again to ensure this pathway is invalid. Additionally, conversion of the nitrile to the aldehydeis currently being attempted, as shown in Figure 4, using formic acid and a platinum catalyst. While platinum is not costeffective, its efficacy is still worth exploring as most other common nitrile to aldehyde conversions have been attempted.
OCH3
HOH
H
N
N
OCH3
HOH
H
Quinine 1,1'-Dideaza-Quinine
+
O
OCH3
H3CO O HO O
I
OO
OO
OOH
OH
HOO
AlCl3
OH3CO H3CO
CNH3CO
CN
H3CO
O
≡
catalyst
1. KOH in (CH2OH)2
2. HCl
1. K2CO3 / KI in EtOAc
2. I2
98%
63%83%
1. Sn(Bu)3H in C6H6
2. 10% KF
60%
37%91%83%
DIBALPCC 1. (Ph)3P=CH2
2. H+
80% 91%
1. TMSCN
2. BF3 etherate (cat.)
chloranil
1,4-dioxane
Overall Yield= 8.6%
OCH3
CN
OCH3
PtO2
60 oC; 7 hr
80% formic acid
O
X
40% KOH
EtOH
H3COCN
H3CO
OHO
H3CO
HN
O
EDC-HCl; HOBt
O NO LiAlH4 H3CO
O
82%
X
OCH3
O
OCH3 O
+OH
H
OCH3 HO
OH
H
OCH3
OH
H
H
HH
-O
enolate
[OH-]
[R]
X Y
O
**
References(1) Stotter, P. L.; Friedman, M. D.; Minter, D. E. J. Org. Chem. 1985, 50 (1), 29–31.(2) Stork, G.; Niu, D.; Fujimoto, R. A.; Koft, E. R.; Balkovec, J. M.; Tata, J. R.; Dake, G. R. Journal of the AmericanChemical Society 2001, 123 (35), 3239–3242.
