GENERAL INTRODUCTION
Manzacidin C - An overview
1.1.1 Characterization, application and scientific reality
Bromopyrrole alkaloids represent a unique group of marine natural products known for their diverse pharmacological activities, including USP7 inhibition, actomyosin ATPase activation, serotonergic receptor antagonism, α-adrenoceptor blocking, antifungal, anti-inflammatory, and antimicrobial properties Additionally, over 140 derivatives with varying structures and biological effects have been isolated from more than 20 different sponge species, as highlighted in a 2014 review by the Rane group on marine bromopyrrole alkaloids.
In 1991, the Kobayashi group first isolated three novel compounds, manzacidins A, B, and C, from the Okinawan sponge Hymeniacidon sp., followed by the isolation of manzacidin D from the coralline demosponge Astrosclera willeyana in 1997 by another research group These compounds represent a unique class of bromopyrrole alkaloids, characterized by their intriguing structures that feature an ester-linked bromopyrrolecarboxylic acid and an unusual tetrahydropyrimidine ring.
Manzacidins have garnered significant interest from the synthetic community due to their unique structures, which feature an extraordinary tetrahydropyrimidine core with two consecutive stereogenic centers and a nitrogen-substituted quaternary carbon center These characteristics suggest that manzacidins could be a rich source of bioactive molecules, similar to other bromopyrrole alkaloids However, their pharmacological potential remains largely unexplored due to limited availability from natural sources, prompting a need for methods to produce them in significant quantities for further study Additionally, the presence of a nitrogen-substituted quaternary carbon stereogenic center in manzacidins is also found in various natural products, making the development of enantioselective synthetic methods for constructing such structural motifs a significant challenge in organic synthesis.
Manzacidins are promising candidates for exploring new synthetic methodologies in the creation of novel structures There has been a growing interest among chemists in achieving enantioselective total synthesis of these compounds Consequently, various research groups have showcased their innovative approaches to synthesize manzacidins, highlighting the effectiveness of new synthetic techniques.
In 2012, the Ohfune group published a comprehensive review on the total synthesis of manzacidins, highlighting their initial synthesis as a valuable guideline for natural product synthesis Since then, significant efforts have been dedicated to achieving enantioselective total synthesis of these compounds.
In the framework of this dissertation, I will focus mainly on previous works for a total synthesis of manzacindin C which is the synthesized target compound of the present study
Seven studies have been conducted on the total synthesis of manzacidin C, highlighting the significance of this research area This article aims to summarize these reports to present a clear understanding of the current scientific advancements related to manzacidin C synthesis.
1.1.2.1 The first total synthesis of manzacidin C by applying Strecker synthesis (Ohfune group)
In 2000, the Ohfune group achieved the first total synthesis of manzacidins A and C, confirming their absolute configurations The synthetic process for manzacidin C consisted of 15 steps, resulting in an overall yield of 3.5%.
Scheme I- 1 The first total synthesis of manzacidin C by applying Strecker synthesis
As shown in Scheme I-1, this route applied the asymmetric Strecker synthesis to construct
The synthesis of (6S)-amino nitrile 4 began with the preparation of the Strecker precursor, D-Phe isomer 2, from (2S)-allylglycinol (1) in three steps The selective removal of the Boc group from D-Phe isomer 2 led to the formation of imine 3 The construction of (6S)-amino nitrile 4 was achieved by adding nitrile to the imine, approaching from the opposite side of the carbon-substituted benzyl group Following this, a lactone was synthesized in 11 steps through the formation of cyclic urea 5 and diol 6 The tetrahydropyrimidine ring was constructed in two steps using trifluoroacetic acid and methylorthoformate Finally, Manzacidin C was obtained by esterifying the tetrahydropyrimidine with bromopyrrolecarboxylate.
1.1.2.2 Total synthesis of manzacidin C using rhodium catalyst by stereospecific C-H bond oxidation (Dubois group)
In 2002, the Dubois group successfully constructed the stereo-framework of manzacidin C through an oxidative C-H insertion of sulfamate esters using Rh catalysis This synthetic process consisted of nine steps and achieved an overall yield of 32%.
Scheme I- 2 Total synthesis of manzacidin C by stereospecific C-H bond oxidation
The hydrogenated product 8 was synthesized via diastereoselective hydrogenation of homoallyl alcohol 7 using Rh[((S,S)-Et-DUPHOS)(cod)]OTf Subsequent sulfamoylation of 8 with ClSO2NCO yielded sulfamate 9, resulting in a diastereomer mixture greater than 95:5 This mixture underwent oxidative cyclization with a catalytic amount of Rh2(OAc)4 and PhI(OAc)2, producing oxathiazinane 10 in a regio- and stereoselective manner The ring-opened product 11 was obtained from 10 through Boc-protection and an SN2-type reaction with sodium azide Finally, the key tetrahydropyrimidine was synthesized from 11 in three additional steps, culminating in the formation of Manzacidin C through an esterification reaction as illustrated in Scheme I-1.
1.1.2.3 Total synthesis of manzacidin C using asymmetric aza-Mannich reaction (Lanter group)
In 2005, the Lanter group demonstrated an innovative approach to the enantioselective total synthesis of manzacidin C through an asymmetric aza-Mannich reaction This method involved the use of chiral sulfinimine anions as nucleophiles and N-sulfonyl aldimines as electrophiles, resulting in a condensation product with high diastereoselectivity and good yield The entire synthetic sequence comprised nine steps, achieving an overall yield of 27%.
Scheme I- 3 Total synthesis of manzacidin C using asymmetric aza-Mannich reaction
As shown in Scheme I-3, -sulfonamido sulfinyl imine 14 was obtained in 85% yield (dr:
>99:1) by the reaction of sulfinyl imine 12 and N-sulfonyl aldimine 13 via deprotonation step of
The synthesis of diamine 15 was achieved through a three-step process starting with lithium bis(trimethylsilyl)amide (LHMDS) This involved the addition of methylmagnesium bromide to the β-sulfonamidosulfinyl imine 14, followed by the deprotection of the sulfinyl group using a mixture of HCl and dioxane, yielding a single diastereomer with a good chemical yield of 65% Subsequently, compound 16 was obtained through two additional steps that included cyclization and the Bus method.
(N-tert-butanesulfonyl) deprotection Construction of the tetrahydropyrimidine was performed via following 3 reactions: ozololysis, oxidation and deprotection, respectively Manzacidin C was finally achieved by the esterification reaction using standard method (Scheme I-1)
1.1.2.4 Total synthesis of manzacidin C based on cycloaddition methodologies (Sibi group and Leighton group) a) Total synthesis of manzacidin A and ( ent )-manzacidin C using Lewis acid-catalyzed asymmetric 1,3-dipolar cycloaddition by Sibi group
In 2007, Sibi group reported an efficient synthesis of manzacidin A and (ent)-manzacidin C based on an enantioselective 1,3-dipolar cycloaddition of a diazoester to a pyrazolidinone imide 9
Scheme I- 4 Total synthesis of manzacidin A and (ent)-manzacidin C using Lewis acid catalyzed asymmetric 1,3-dipolar cycloaddition
The cycloaddition of ethyl diazoacetate to unsaturated pyrazolidinone imide resulted in a high-yield cycloadduct, achieving 99% yield and 97% enantiomeric excess with the aid of Mg(NTf2)2 and a chiral ligand Subsequent reactions transformed the cycloadduct into an amino alcohol, which was then treated with trimethyl orthoformate to construct the desired tetrahydropyrimidine core This core was further processed using Raney nickel and hydrogen, leading to the esterification with 4-bromo-2-trichloroacetylpyrrole, ultimately yielding an 85:15 diastereomeric mixture of manzacidin A and (ent)-manzacidin C Additionally, the total synthesis of manzacidin C was achieved through chiral silicon-based Lewis acid-promoted asymmetric [3+2] cycloaddition as demonstrated by the Leighton group.
In 2008, the Leighton group achieved a significant milestone by reporting the first synthesis of manzacidin C through a chiral silicon-based Lewis acid-promoted asymmetric [3+2] cycloaddition This innovative synthetic route consisted of six steps and yielded an overall 26% Notably, this synthesis uniquely constructs the C(4) and C(6) stereocenters in a single step with high stereoselectivity, marking a breakthrough in the synthesis of manzacidins.
Scheme I- 5 Total synthesis of manzacidin C using chiral silicon-based Lewis acid promoted asymmetric [3+2] cycloaddition
As shown in Scheme I-5, 24 was constructed in 73% yield with excellent selectivity (>20:1), and 94% ee by the cycloaddition reaction of 21 and 22 promoted by the optically active silane
General aspects for the 1,3-dipolar cycloaddition reaction
This section outlines the importance of 1,3-dipolar cycloaddition reactions in organic synthesis, providing a foundational understanding for the current study's orientation.
The 1,3-dipolar cycloaddition reaction has been extensively studied, leading to the development of a wide variety of reactions and applications A significant amount of literature, including textbooks, research articles, and reviews, has been published on this topic This article aims to highlight the fundamental aspects of 1,3-dipolar cycloaddition based on the existing body of research.
1.2.1 The role of the 1,3-dipolar cycloaddition
The 1,3-dipolar cycloaddition reaction is a fundamental process in modern synthetic organic chemistry, recognized for its effectiveness in constructing heterocycles with varying complexities This reaction is particularly significant for synthesizing five-membered heterocyclic rings, which are prevalent in a wide array of valuable chemicals, including pharmaceuticals, agrochemicals, and naturally occurring bioactive compounds.
The 1,3-dipoes have already recognized and described in reported literatures as follows
1,3-dipoles are composed of elements from main groups IV, V, and VI, with the primary dipole featuring elements from the second row, specifically nitrogen (N) or oxygen (O) as the central atom Consequently, the variety of structures that can be generated is restricted to combinations of nitrogen, carbon (C), and oxygen.
If higher row elements are excluded, twelve allyl anion type and six propargyl - allenyl anion type 1,3-dipoles can be obtained, (Figure I-2)
The most common dipolarophiles are also well-determined and they involve some types which are listed as the below
1) Multiple-bonded hydrocarbons (i.e alkenes and alkynes)
3) Unsaturated compounds containing heteroatoms (i.e allylic alcohols, allylic halides, vinylic ethers, imines, nitriles, nitroso, azo)
The 1,3-dipolar cycloaddition mechanism has been thoroughly studied and is characterized as a concerted reaction, where the orbitals of the dipole and dipolarophile overlap The transition state of this reaction is governed by the frontier molecular orbitals (FMO) of the involved substrates, with the LUMO of the dipole interacting with the HOMO of the alkene, and the HOMO of the dipole interacting with the LUMO of the alkene.
The 1,3-dipolar cycloaddition reactions are classified into three types based on the relative FMO energies between the dipole and the dipolarophile, 14 (Figure I-3)
Figure I- 3 FMO diagram of 1,3-dipolar cycloaddition reaction
Type I: The dominant FMO interaction is that of the HOMO of dipole with the LUMO of dipolarophile
Type II: The similarity of the dipole and dipolarophile FMO energies implies that both HOMO-LUMO interactions are important
Type III: Cycloaddition reactions are dominated by the interaction between the LUMO of dipole and the HOMO of dipolarophile
Figure I-4 illustrates the reactions of dipolars forming five-membered rings, specifically involving allyl and propargyl/allenyl anions In concerted 1,3-dipolar cycloaddition reactions with 1,2-disubstituted alkenes, two new chiral centers are generated in a stereospecific manner due to the syn attack on the double bond This process ensures that the stereochemistry at C-4 and C-5 is determined by the geometric arrangement of the substituents on the alkene Depending on the dipolar structure and reaction conditions, such as temperature and solvent, it is possible to create up to four new contiguous chiral centers in a single reaction.
Figure I- 4 An illustration for the 1,3-dipolar cycloaddition reaction
1.2.5 Advantages and drawbacks of the 1,3-dipolar cycloaddition
1.2.5.1 Advantages of the 1,3-dipolar cycloaddition
The highlights of the 1,3-dipolar cycloaddition have been studied as follows
1) The 1,3-dipolar cycloadditions are considered as the most prevalent and useful method for the construction of novel five-membered heterocycles
2) These reactions are amenable to Lewis acid catalyst and can be carried under mild conditions to control the selectivity (i.e regioselectivity, diastereoselectivity, and enantioselectivity)
3) The bond formation, ring construction, stereoselectivity manner could be well-controlled in a single operation with high levels
1.2.5.2 Drawbacks of the 1,3-dipolar cycloaddition
The main drawbacks of the 1,3-dipolar cycloaddition were also realized as follows:
1) The use of 1,3-dipolar cycloaddition may be difficult to directly generate larger or smaller rings
2) Harsh conditions may be required for these reactions (high temperature, prolong reaction time, etc.)
3) Sensitive and unstable substrates (i.e azomethine imines) are probably not withstand with the harsh reaction conditions
4) Products are usual generated in an racemic form if a certain control is not imposed on the 1,3-cycloaddition reaction
1.2.6 Conclusion for general aspects of the 1,3-dipolar cycloaddition
Concerted cycloaddition reactions are a powerful method for controlling selectivity in organic molecules, including regioselectivity, diastereoselectivity, and enantioselectivity A significant challenge in 1,3-dipolar cycloaddition reactions is achieving absolute stereoselectivity, with chiral catalysts proving essential for addressing this issue However, the development of metal-catalyzed asymmetric 1,3-dipolar cycloaddition reactions involving various dipoles remains in its early stages Consequently, this research area is poised for continued growth, offering promising opportunities for chemists in the future.
Our previous works - Research background
This section summarizes key findings from our research group's original papers and reviews, serving as a foundational background for the current study It is important to highlight that certain fundamental concepts and hypotheses are included here as verbatim reprints, in accordance with an agreement within our research group.
In our research, we have developed a novel asymmetric reaction system utilizing multi-metal centers and tartaric acid ester as a chiral auxiliary to facilitate the construction of optically active heterocycles through asymmetric metal-catalyzed 1,3-dipolar cycloaddition reactions This innovative approach has led to significant advancements in asymmetric Simmons-Smith reactions, asymmetric 1,3-dipolar cycloaddition reactions, and asymmetric nucleophilic additions Our focus is primarily on the recent progress in asymmetric cycloaddition reactions involving nitrile oxides, nitrones, and azomethine imines, which are crucial to our study.
1.3.1 Concepts for an asymmetric 1,3-dipolar cyloadditions based on chiral multinucleating system utilizing tartaric acid esters
Our chiral multinucleating system, based on tartaric acid esters, features two metal centers that facilitate the binding of reactants A and B This configuration can lead to the formation of a rigid 5/5-fused bicyclic dinucleating structure, optimizing the orientation and activation of the reactants for subsequent reactions As illustrated, the system allows for regio-, stereo-, and enantioselective reactions, yielding optically active products Additionally, a third metal center can be introduced through the coordination of ester carbonyl and alkoxide oxygens, enabling reactant C to participate in the reaction process.
Figure I- 5 (A, B) Illustration for the concept of an asymmetric 1,3-dipolar cyloaddition on the basic of chiral multinucleating system utilizing tartaric acid esters
1.3.2 Asymmetric 1,3-dipolar cycloaddition of nitrile oxides and nitrones
Between 1993 and 2000, our research group focused on the asymmetric 1,3-dipolar cycloaddition of nitrile oxides and nitrones, with key findings summarized in Scheme I-9 and I-10, including equations I-1, I-2, and I-3.
1.3.2.1 Asymmetric 1,3-dipolar cycloaddition of nitrile oxides
In the asymmetric 1,3-dipolar cycloaddition of nitrile oxides, nitrile oxide is generated in situ from hydroximoyl chloride through treatment with ethylzinc as a base The coordination of nitrile oxide to chiral zinc species is expected to effectively control the stereochemical outcome, with intermediates proposed as 40 and 41 This approach successfully led to the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to allylic alcohols 39, yielding the corresponding 2-isoxazolines 42 with excellent enantioselectivities.
The use of a catalytic amount of diisopropyl (R,R)-tartrate [(R,R)-DIPT] in the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to allyl alcohol (39A) resulted in the formation of 2-isoxazolines 42A with selectivity reaching up to 93% ee, aided by a small addition of 1,4-dioxane This innovative approach represents the first catalytic enantioselective 1,3-dipolar cycloaddition of nitrile oxides with alkenes and has been successfully utilized in the total synthesis of (–)-lasubine II.
Scheme I- 9 Application of the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to the total synthesis of (–)-lasubine II
1.3.2.2 Asymmetric 1,3-dipolar cycloaddition of nitrones
The asymmetric 1,3-dipolar cycloaddition of nitrones, particularly those with an amide moiety, was successfully achieved by reacting them with allylic alcohols to produce 3,5-cis-isoxazolidines with exceptional regio-, diastereo-, and enantioselectivities exceeding 99% ee This method was utilized in the synthesis of the (2S,4R)-4,5-dihydroxynorvaline derivative, a crucial component in various applications.
Polyoxin E, via amino alcohol intermediate 45 (Scheme I-10).17a, 19, 20
Scheme I- 10 Application of the asymmetric 1,3-dipolar cycloadditions of nitrones to the synthesis of a key component of polyoxin E
1.3.3 Asymmetric 1,3-dipolar cycloaddition of azomethine imines
Despite the advancements in cycloadditions involving nitrones with nitrogen and oxygen, the cycloaddition of 1,3-dipoles containing two nitrogen atoms remains underexplored Consequently, our research group has focused on the enantioselective 1,3-dipolar cycloaddition of azomethine imines as a key area of interest in our ongoing research efforts.
Between 2008 and 2014, we successfully developed asymmetric 1,3-dipolar cycloadditions of azomethine imines with various alcohols, resulting in the formation of optically active pyrazolidines This article will provide a detailed overview of these significant findings.
1.3.3.1 Asymmetric 1,3-dipolar cycloaddition of azomethine imines to allyl alcohol
The study focused on the 1,3-dipolar cycloaddition of 1-alkylidene-3-oxopyrazolidin-1-ium-2-ide 47, revealing that a magnesium-mediated system was more effective than a zinc-mediated one for achieving asymmetric cycloaddition The reaction involved the sequential addition of alkylmagnesium bromide and azomethine imines 47 to a mixture of allyl alcohol (39A) and (R,R)-DIPT This method yielded pyrazolidines 48 with good chemical yields (50-81%) and excellent enantioselectivities (88-96%) across various substrates, including both aromatic and aliphatic azomethine imines 47 (Scheme I-11).
Scheme I- 11 Stoichiometric asymmetric 1,3-dipolar cycloaddition of azomethine imines to allyl alcohol
Our research group has enhanced the catalytic reaction system (Scheme I-12) to achieve higher enantioselectivity The key improvements included the addition of an equimolar amount of MgBr2 and the utilization of alkylmagnesium chloride as a Grignard reagent to produce magnesium alkoxides, which significantly boosted enantioselectivity We successfully conducted the catalytic asymmetric cycloaddition of various azomethine imines, including aryl-substituted and those with pentyl, cyclohexyl, or t-butyl groups, to allyl alcohol (39A) The resulting cycloadducts exhibited good to high chemical yields (54-74%) and very high enantioselectivities (81-93%).
Scheme I- 12 Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine imines to allyl alcohol
1.3.1.2 Asymmetric 1,3-dipolar cycloaddition of azomethine imines to 1,4-pentadien-3-ol
Next, the present method was applied to control stereochemistry of mutichiral carbon centers
In a study involving the prochiral divinylcarbinol, 1,4-pentadien-3-ol (49), it was demonstrated that asymmetric 1,3-dipolar cycloaddition through desymmetrization successfully produced optically active pyrrazolizines (50) These compounds exhibited three chiral centers with complete diastereoselectivity, yielding excellent results with yields ranging from 75% to 98% and enantioselectivity at 99% However, a lower chemical yield of 33% was observed with a pentyl substituent, while a t-butyl substituent showed a high enantioselectivity of 92%.
Scheme I- 13 Stoichiometric asymmetric 1,3-dipolar cycloaddition of azomethine imines to 1,4-pentadien-3-ol
As shown in Scheme I-14, the catalytic version using 0.2 equiv of (R,R)-DIPT, chemical yields were not satisfactory (13-75%) However, enantioselectivities were still excellent by the addition of MgBr2 (79-98%)
Scheme I- 14 The catalytic asymmetric 1,3-dipolar cycloaddition of azomethine imines to 1,4-pentadien-3-ol
1.3.1.3 Asymmetric 1,3-dipolar cycloaddition of azomethine imines to homoallylic alcohols
To synthesize optically active nitrogen-containing chemicals with oxygen functionalities, employing unsaturated alcohols as 1,3-dipolarophiles is ideal Our research group has developed both stoichiometric and catalytic asymmetric 1,3-dipolar cycloaddition methods using azomethine imines with one-carbon homologated homoallylic alcohols.
The asymmetric 1,3-dipolar cycloaddition of azomethine imines to homoallylic alcohols was successfully investigated, resulting in the formation of corresponding products with high to excellent yields ranging from 71% to 85% and enantioselectivities between 91% and 99% However, a low chemical yield of 24% was observed when a pentyl substituent was used.
Scheme I- 15 Stoichiometric asymmetric 1,3-dipolar cycloaddition of azomethine imines to homoallylic alcohol
The addition of MgBr2 significantly improved enantioselectivities in the catalytic version, achieving excellent results with aryl-substituted azomethine imines (93-94%) Cycloaddition reactions involving pentyl-, cyclohexyl-, and t-butyl-substituted azomethine imines exhibited moderate to good enantioselectivities ranging from 65% to 83% Additionally, chemical yields were generally high, between 72% and 90%, although a lower yield of 23% was observed for the pentyl substituent.
Scheme I- 16 Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine imines to homoallylic alcohol
Research orientation
In light of the increasing focus on the total synthesis of natural compounds, particularly manzacidins and specifically manzacidin C, we proposed that using sterically demanding alcohols, such as methallyl alcohol, as a 1,3-dipolarophile in an asymmetric 1,3-dipolar cycloaddition with azomethine imines and diisopropyl (S,S)-tartrate as a chiral auxiliary could yield pyrazolidines with a chiral quaternary carbon If successful, this approach could lead to the synthesis of pyrazolidine 54 when azomethine imine 47a is employed This strategy is relevant for synthesizing manzacidin C, as both the resulting pyrazolidine and manzacidin C share the same stereochemical framework.
Figure I- 6 Envisaged synthetic methodology for the synthesis of manzacidin C
According to above mentions, I wish to pursuit these challenges with an aspiration to be able to contribute a new synthetic methodology regard to the research fields.
Research objective
Based on relevant previous studies, the context of the research areas, and compelling scientific data, this study aims to establish clear objectives for further exploration.
1) Direct construction of optically active pyrazolidines possessing a nitrogen substituted a chiral quaternary carbon center in high chemical yields, excellent enantioselectivities and complete diastereoselectivities by asymmetric 1,3-cycloaddition reactions of azomethine imines to methallyl alcohol
2) Development of an efficient synthetic methodology for the total synthesis of manzacidin C based on the developed asymmetric 1,3-cycloadition reactions.
HIGHLY ENANTIOSELECTIVE 1,3-DIPOLAR CYCLOADDITION OF
Enantioselective 1,3-dipolar cycloaddition of azomethine imines to methallyl alcohol (Initial procedure)
Our research group has successfully demonstrated the 1,3-dipolar cycloaddition of azomethine imines to various alcohols, including allyl alcohol and homoallylic alcohols, as detailed in Chapter 1, Section 1.3.3 The process involved treating a mixture of alcohol and (R,R)-DIPT with a Grignard reagent, followed by the addition of an azomethine imine We optimized several reaction conditions, including the choice of Grignard reagents (RMgBr or RMgCl), solvents (MeCN or EtCN), temperature (0-80 °C), and reaction time (2-5 days), which resulted in the formation of pyrazolidines with excellent enantioselectivities This study marks the first application of our previous procedure to the 1,3-dipolar cycloaddition of azomethine imines to methallyl alcohol.
First, the asymmetric 1,3-dipolar cycloaddition of azomethine imine 47a to methallyl alcohol
The study investigated the use of tartaric acid ester (DIPT) as a chiral auxiliary, following a previously established method The procedure involved mixing methallyl alcohol with (R,R)-DIPT in a solvent, treating the mixture with a Grignard reagent, and subsequently adding azomethine imine at 0 °C The reaction was then heated to 80 °C for five days.
The optimization of reaction conditions involved screening halogens in Grignard reagents, selecting appropriate solvents, adjusting the amount of alcohol used, and determining the addition method for azomethine imines The findings from this optimization process are detailed in Table II-1, Entries 1-7.
A mixture of methallyl alcohol (53) and (R,R)-DIPT in MeCN was treated with MeMgBr, followed by the addition of azomethine imine 47a at 0 °C, and then heated to 80 °C The cycloaddition reaction proceeded slowly, yielding pyrazolidine 54a as a single diastereomer in moderate yield (48%) and high enantioselectivity (90% ee) after 5 days To improve the chemical yield, a trial with 2.0 equivalents of alcohol 53 was conducted; however, this resulted in lower yields (42%) and enantioselectivity (50% ee) compared to the initial reaction using 1.0 equivalent of 53.
To enhance chemical yield, we investigated the effects of halogens in Grignard reagents and solvents on the reaction outcomes Notably, as indicated in Table II-1, Entry 3, the use of alcohol 53 (1.0 equiv) with n-BuMgCl (3.0 equiv) in the solvent C2H5CN resulted in a cycloadduct 54a with a yield of only 20% and an enantiomeric excess (ee) of 82%.
Table II- 1 Optimization of reaction conditions for the 1,3-dipolar cycloaddition
We examined the effects of alcohol quantity and the method of adding azomethine imines to the reaction mixture Using 2.0 equivalents of alcohol and adding azomethine imine in a suspension state resulted in a moderate yield of cycloadduct 54a (47%) with an enantiomeric excess of 82% However, when azomethine imine was added slowly as an EtCN solution, the yields improved significantly to 57-61%, and the enantioselectivities also increased slightly to 82-85%.
The study examined the impact of reaction scale on the 1,3-dipolar cycloaddition of azomethine imine 47a In larger scale reactions, 17.0 mmol of azomethine imine was gradually added as a solid, with 2.0 equivalents of alcohol 53 utilized This approach resulted in a smoother reaction process, yielding cycloadduct 54a with an improved yield of 66% and an enantiomeric excess (ee) of 87%.
Based on the examined reactions under various conditions, these results suggest that the chemical and optical yields fluctuated
2.1.3 Scope of substrates (Initial procedure)
Next asymmetric cycloaddition of several azomethine imines 47 to methallyl alcohol (2.0 equiv) was performed in EtCN at 80 o C The general procedure was that:
A solution of methallyl alcohol (0.44 g, 6.0 mmol) in EtCN (5.0 mL) and (R,R)-DIPT (0.704 g, 3.0 mmol) in C2H5CN (5.0 mL) was treated with ethylmagnesium chloride (12.8 mL of a 0.94 M solution in THF, 12.0 mmol) at 0 °C under an argon atmosphere The mixture was stirred for 1 hour at 0 °C, followed by the addition of azomethine imine 47a (3.0 mmol, 1.0 equiv.) in EtCN The reaction proceeded with stirring at 0 °C for an additional hour, then at room temperature for 1 hour, and finally at 80-90 °C for 5 days.
The reaction was quenched using a saturated aqueous solution of NH4Cl, followed by extraction with CHCl3 and H2O The combined extracts were dried over Na2SO4 and concentrated under reduced pressure The residue underwent purification via column chromatography using a gradient of hexane and AcOEt, yielding the desired pyrazolidine 54a Similarly, pyrazolidines 54b-54e were synthesized from azomethine imines 47b-47e, with results detailed in Table II-2, Entries 1-6.
Table II- 2 Scope of substrates under optimized conditions of the initial procedure
Among substrates used, aryl-substituted azomethine imine 47a and 47b realized good yield
(almost 60%) and high ee (82-91%), (Table II-2, Entries 1-3) In the case of 4-chlorophenyl- substituted azomethine imine 47c, the cycloadduct 54c was obtained in slightly decreased yield
(50%) and ee (81%) The cycloaddition of a cyclohexyl-substituted azomethine imine 47d afforded 54d in 60% yield and with lower ee (77%) A t-butyl-substituted azomethine imine 47e resulted in high yield (74%) and ee (83%)
2.2 Highly enantioselective 1,3-dipolar cycloaddition of azomethine imines to methallyl alcohol (Improved procedure)
Most chiral drugs must be administered in their enantiomerically pure form to ensure safety, making it essential to enhance the enantioselectivity during asymmetric synthesis.
The development of a 1,3-dipolar cycloaddition involving phenyl-substituted azomethine imine and methallyl alcohol using (S,S)-DIPT aims to synthesize the bioactive compound manzacidin C To achieve this, it is essential that the resulting pyrazolidine possesses the stereochemical framework of manzacidin C with a high enantiomeric excess Consequently, efforts were made to enhance the synthetic procedure of the asymmetric 1,3-dipolar cycloaddition to produce enantiomerically pure compounds.
In our enhanced method, we identified that the optimal approach involves adding the Grignard reagent last to the mixture of azomethine imine 47a, methallyl alcohol (53), and chiral DIPT, rather than incorporating it during the middle stage as outlined in the original procedure.
The general procedure was that: to a mixture of azomethine imine possessing a pyrazolidinone skeleton 47 (1.0 equiv) and DIPT (y equiv) was added an MeCN solution of methallyl alcohol
Under an argon atmosphere, a specific amount of solvent was added to the reaction mixture, which was stirred at room temperature for 30 minutes before being cooled to 0 °C A Grignard reagent was then gradually introduced to the mixture, followed by stirring at 0 °C for 30 minutes, at room temperature for 1 hour, and finally at 80 °C for 7 days.
The reaction was quenched using a saturated aqueous solution of NH4Cl, followed by extraction with CHCl3 The combined extracts were dried with Na2SO4 and concentrated under reduced pressure The resulting residue underwent purification through column chromatography using SiO2 and a solvent gradient of Hexane/AcOEt and AcOEt/MeOH, yielding the desired pyrazolidine The enantiomeric excess (ee) was assessed via HPLC using the Daicel CHIRALPAK IA column.
2.2.2 Optimization of reaction conditions for the 1,3-dipolar cycloaddition
The optimization of the reaction conditions is summarized in Table II-3, Entries 1-9
Table II- 3 Optimization of reaction conditions for the 1,3-dipolar cycloaddition
As shown in Table II-3, Entries 1-2, when alcohol 53 (1.0 equiv), n-BuMgCl (3.0 equiv),
(S,S)-DIPT (1.0 equiv) and solvents (EtCN, MeCN) were subjected to the asymmetric 1,3- dipolar cycloaddition The reactions smoothly proceeded to furnish the corresponding products
54a in moderate yields (57-59%) and with very high ee (91-94%), respectively The used solvents slightly influenced the reaction
As shown in Table II-3, Entries 3-5, we examined an another Grignard reagent, n-PrMgBr
Freshly prepared n-PrMgBr solutions (1 M, 1.8 M, or 2 M) in THF were directly added to the reaction mixture, following an improved procedure Notably, using 2 M n-PrMgBr resulted in a cycloadduct with a commendable chemical yield of 77% and high enantioselectivity at 97% However, the reproducibility was inconsistent, with yields varying between 57% and 77% and enantiomeric excess (ee) ranging from 95% to 97%, likely due to moisture affecting the freshly prepared Grignard reagent To streamline the synthetic process, commercially available Grignard reagents were employed for the 1,3-dipolar cycloaddition, as demonstrated in Entries 6-9.
Determination of absolute stereochemistry of the cycloadduct
The recrystallization of cycloadduct 54a, derived from (S,S)-DIPT, achieved an optical purity of 99.4% ee This enantiomerically enriched compound was then reacted with (S)-1-phenylethyl isocyanate in the presence of a catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP), yielding the corresponding carbamate 55a in quantitative yield Further recrystallization from AcOEt resulted in diastereomerically pure 55a The absolute stereochemistry of the pyrazolidine framework in 55a was confirmed as S,S through X-ray crystallographic analysis of its single crystal.
Scheme II- 1 Determination of absolute stereochemistry of 54a
The cycloadduct 54e, with an enantiomeric excess of 83%, was successfully converted to the carbamate 55e, achieving a yield of 72% The absolute configuration of the pyrazolidine skeleton in 55e was definitively established as R,R through single-crystal X-ray diffraction analysis of the diastereomerically pure compound obtained from recrystallization.
AcOEt, (Scheme II-2) The absolute configurations putatively assigned to the other products
54b–54d by the use of (R,R)-DIPT were R,R
Scheme II- 2 Determination of absolute stereochemistry of 54e.
Proposed transition state model
The transition state of the 1,3-dipolar cycloaddition remains uncertain, but models based on the configurations of compounds 54a and 54e, along with previous findings, suggest possible pathways In this process, the carbonyl oxygen of azomethine imine 47 interacts with the magnesium salt of (R,R)-DIPT, while the nitrogen atom linked to the carbonyl attacks the disubstituted internal olefinic carbon of methallyl alcohol (53) rather than the monosubstituted internal carbon Assuming a cycloaddition from the Si-face of methallyl alcohol, the azomethine imine and the double bond are positioned in a skewed manner, complicating their overlap Conversely, when considering the Re-face addition, the exo-transition state T2 is likely unfavorable due to steric hindrance, leading to the cycloaddition proceeding in an endo-fashion to form the (R,R)-cycloadduct 54.
Figure II- 1 Proposed transition state model.
The first retrosynthetic plan of manzacidin C
We first under took a retrosynthetic analysis of manzacidin C, as illustrated in Scheme II-3
Scheme II- 3 The first retrosynthetic plan of manzacidin C
The synthesis of (S,S)-2,4-diamino-2-methylbutan-1-ol (B) can be achieved using (S,S)-DIPT via cycloadduct 54a Additionally, oxidizing the phenyl ring can facilitate the formation of the carboxylic acid functionality (A) Subsequently, Manzacidin C can be obtained through a series of transformations.
The synthesis of manzacidin C relies on the critical removal of a three-carbon bridge between two nitrogens in the pyrazolidine ring C3 unit To achieve this, we have explored various synthetic methods, which are detailed in Chapter III.
Summary for chapter II
We have successfully developed an asymmetric 1,3-dipolar cycloaddition of azomethine imines to methallyl alcohol, enabling the construction of optically active pyrazolidines in a single step This process achieves complete diastereoselectivity, excellent enantioselectivity, and yields ranging from good to high Furthermore, we propose the application of this innovative 1,3-dipolar cycloaddition for the synthesis of the natural product manzacidin C.
DIVERSE APPROACHES FOR THE REMOVAL OF THREE-CARBON
Removal strategy of the C3 unit via an oxidation of hydrazine moiety in the produced
Scheme III- 1 Expected synthetic pathway
The synthesis involves three key steps: first, the protection of the hydroxyl group in compound 54a to form compound 56; second, the oxidation of the hydrazine moiety in compound 56 to yield compound 57; and finally, the elimination under basic conditions to produce the target compound, as illustrated in A-1.
3.1.1 Protection of the hydroxyl group and oxidation of hydrazine moiety in 54a
Scheme III- 2 Protection of a hydroxyl group and an oxidation of a hydrazine moiety
The synthesis process began with the construction of hydrazine oxide 57, starting with the protection of the hydroxyl group in compound 54a using tert-butyldimethylsilyl chloride (TBSCl), which resulted in an excellent yield of 96% for compound 56 Subsequently, the OH-protected compound 56 underwent oxidation with m-chloroperoxybenzoic acid (m-CPBA), yielding the hydrazine oxide derivative 57 with a high chemical yield of 90%.
3.1.2.1 Elimination reaction of 57 under basic conditions
With 57 in hand, we started an elimination reaction under basic conditions The results of the examined reactions are summarized in Table III-1
Lithium diisopropylamide (LDA) was initially tested for the elimination reaction of compound 57, but the reaction failed to proceed at temperatures ranging from -78 to -40 °C, resulting in the recovery of nearly all starting material Subsequent experiments at higher temperatures also did not yield the anticipated compound 58; instead, an unexpected elimination product 59 and several unidentified byproducts were formed, with only 15% of the starting material recovered.
The investigation of potassium hexamethyldisilazide (KHMDS) revealed similar outcomes as seen in previous experiments; specifically, the anticipated compound 58 was not produced, and various byproducts consistently emerged.
Table III- 1 Examination of various bases on the elimination reaction of 57
3.1.2.2 Elimination reaction of 57a under basic conditions
Increasing the cationic counterion property of the nitrogen atom in the hydrazine moiety can enhance the expected elimination reaction To explore this, we converted the hydrazine oxide derivative 57 into 57a using trimethyloxonium tetrafluoroborate, also known as the Meerwein reagent.
The examination results are illustrated in Scheme III-3, where compound 57 was converted to 57a and subsequently underwent elimination without additional purification However, the anticipated compound 58 was not produced; instead, compounds 54a and 56 were formed, along with unidentified byproducts confirmed through 1H NMR analysis.
Scheme III- 3 Transformation of 57 to 57a towards the elimination reaction
3.1.3 Conclusion for the synthetic route 1
Despite conducting multiple experiments, the results revealed unexpected elimination compounds, likely due to the deprotonation of the benzylic proton in the formed cycloadduct Therefore, it is essential to explore alternative synthetic routes.
Removal strategy of the C3 unit via an introduction of a double bond into
Scheme III- 4 Expected synthetic pathway
As shown in Scheme III-4, the expected synthetic pathway of this route is illustrated In this approach, the planned synthesis includes following steps: (1) Sulfenylation and oxidation to give
62 (2) Elimination to give 63 (3) Further transformations relying on the introduced double bond to give the target compound as shown in A-1
3.2.1 Introduction of the double bond into the pyrazolidinone moiety
The introduction of a double bond into the pyrazolidinone moiety was initiated through a sulfenylation reaction Optimization of this reaction involved screening various factors affecting productivity, including the amounts of reagents (base and electrophile), reaction temperature, and reaction time, with the results detailed in Table III-2.
Under examined conditions, desired compound 60 was obtained along with the formation of
61 With the examined conditions as shown in Table III-2, Entry 5, the desired compound 60 could be obtained in 71% Thus, these conditions were chosen as the optimization conditions for the sulfenylation reaction
Table III- 2 Optimization of reaction conditions for the sulfenylation
The introduction of a double bond into the pyrazolidinone moiety was achieved through oxidation and dehydrosulfenylation reactions, with the outcomes detailed in Table III-3, Entries 1-4.
The oxidation of compound 60 using m-CPBA results in the formation of compound 62, which is subsequently subjected to dehydrosulfenylation with pyridine under reflux in toluene, yielding the desired compound 63 Additionally, during the reaction process, byproducts 62A and 64 are generated in accordance with each reaction step.
The optimization conditions were finally chosen as highlighted in Table III-3, Entry 4 By these conditions, the oxidation and dehydrosulfenylation reactions were conducted in a sequence to afford 63 in 89% yield
Table III- 3 Optimization of reaction conditions for the oxidation and dehydrosulfenylation
3.2.2 Diverse transformations relying on the introduced double bond
The incorporation of a double bond into the pyrazolidinone structure of cycloadduct 56 led to the formation of compound 63, which features various functional groups, including an enamine, alkene, amine, and amide carbonyl This diverse array of functional groups in compound 63 enabled a range of subsequent transformations, which are detailed in the following sections.
3.2.2.1 Transformation relying on an enamine functional group a) Hydrolysis reaction
Scheme III- 5 Examination for a hydrolysis of an enamine functional group
In Scheme III-5, the hydrolysis of an enamine functional group in compound 63 using 1 M HCl was initially investigated, leading to the formation of compound 64 through the deprotection of the TBS-protected group in an acidic environment However, when compound 64 was treated with concentrated HCl for further hydrolysis, the reaction did not occur.
3.2.2.2 Transformation relying on hydroxylamine and enamine functional groups
Scheme III- 6 Expected synthetic pathway
In our research, we aimed to synthesize compound 65, which features hemiaminal and enamine functional groups, by reducing the amide carbonyl in compound 63 Successfully creating compound 65 would enable us to explore its potential for further transformations, including hydrolysis.
The target compound, as illustrated in A-1, is achieved through the reaction of the introduced hemiaminal with a hydrazine agent, resulting in the formation of 65A This intermediate is subsequently hydrolyzed to yield the desired compound A-1.
The reduction of the amide carbonyl in 63 was first examined The results of these examinations are summarized in Table III-4
Table III- 4 Examination for the introduction of the hydroxyl group by the reduction of the amide carbonyl in 63
Table III-4 illustrates that the reduction was performed under various conditions (Entries 1-4) Notably, compound 65 was undetected, while nearly all starting material was recovered when diisobutylaluminium hydride (DIBAL-H) was employed In contrast, the use of lithium aluminum hydride (LiAlH4) resulted in a complex mixture.
3.2.2.3 Transformation relying on an alkene functional group
The expected synthetic pathway for removing the C3 unit involves utilizing an alkene functional group in compound 63 We anticipate that compound 66 can be synthesized through oxidative cleavage of the double bond in 63 This method allows for subsequent transformations to achieve the target compound, as illustrated in A-1, with the oxidative cleavage being facilitated by an ozonolysis reaction.
Scheme III- 8 Examination for the oxidative cleavage reaction by an ozonolysis reaction
The oxidative cleavage of the double bond was initially investigated through ozonolysis reactions, as illustrated in Scheme III-8 Contrary to expectations, the anticipated compound 66 was not produced; instead, a complex mixture resulted Additionally, the oxidative cleavage of the double bond was also explored using a periodate reagent.
A report by the Horst Weber group highlights the successful oxidative ring-opening of pyrazolone derivatives using NaIO4 in a MeOH/H2O solvent system Following this, the oxidative cleavage of the double bond in compound 63 was explored using NaIO4 as per the established procedure Unfortunately, the anticipated compound 66 was not obtained in this reaction.
64 was generated in 94% (Entry 1) To our surprise, 67 was detected in 25% yield (Entry 2)
Scheme III- 9 Examination for the oxidative cleavage reaction using a periodate agent
The hydrolysis reaction of compound 67 was studied, as it was hypothesized that the presence of an electron-withdrawing group, specifically iodine, would enhance the reaction Consequently, the reduction yielded compound 64, while the anticipated compound 66 was not observed Additionally, oxidative cleavage of the double bond was achieved using potassium permanganate and sodium periodate.
The oxidative cleavage of the double bond was investigated using potassium permanganate and sodium periodate, based on a report by the Zhang group This process led to a hydrolysis reaction, resulting in compound 64, while the anticipated compound 66 was not detected.
Scheme III- 10 Examination for the oxidative cleavage reaction using potassium permanganate and sodium periodate
3.2.3 Conclusion for the synthetic route 2
The synthetic route allows for precise control over the introduction of double bonds, leading to various subsequent transformations, including hydrolysis, reduction, and oxidative cleavage reactions These reactions often yield unexpected compounds, while the starting materials are frequently recovered The low reactivity observed is likely attributed to the aromaticity of the compounds resulting from the double bond introduction.
Removal strategy of the C3 unit via an introduction of bis(methylthio-) substituted in
Scheme III- 11 Expected synthetic pathway
As shown in Scheme III-11, an expected synthesis route for the removal strategy of the C3 unit via an introduction of bis(methylthio-) substituted in the pyrazolidinone moiety is illustrated
In this approach, the synthesis involves following steps: (1) Preparation of bis(methylthio-) substituted in the pyrazolidinone moiety 61 (2) Hydrolytic cleavage of dithioacetal in 61 to give
68 (3) Introduction of a hydroxyl group relying of the newly formed ketone group in 68 to give 68A (4) Further transformations to give the target compound as shown in A-1
The synthesis started with the preparation of 61 The synthetic procedure of 61 was revised based on those as mentioned in Section 3.2.1.1 Thus, 61 could be prepared in 87% yield via the
With 61 in hand, the hydrolytic cleavage of the dithioacetal in 61 was performed and these results are given in Table III-5
Table III- 5 Results of the hydrolytic cleavage of the dithioacetal in 61
Table III-5 displays the screening of various reagents for the hydrolytic cleavage of dithioacetal, revealing that the anticipated compound 68 was not produced Instead, unexpected compounds 69, 69A, 70, and 71 were formed.
In order to make good use of unpredictably obtained compounds, many transformations were executed as shown in the following sections
3.3.3 Transformations based on functional groups resulting from the oxidative hydrolysis of the dithioacetal in 61
3.3.3.1 Transformation via the hydrolysis of 71
The compound 71 from the oxidative hydrolysis of dithioacetal was obtained in almost 60%
This compound was subjected to a hydrolysis, as shown in Scheme III-13
Scheme III- 13 Examination for a hydrolysis reaction of 71
The presence of a stronger electron-withdrawing group, such as methylsulfinyl in compound 71, is expected to facilitate the hydrolysis reaction, potentially yielding the target compound A-2 However, as noted in Section 3.2.2.3, the reaction instead led to desulfenylation, resulting solely in the formation of compound 64.
3.3.3.2 Transformations via an introduction of a hydroxyl group into 70
The compound 70 from the oxidative hydrolysis of the dithioacetal could be obtained in almost 63% yield Due to the electronic resonance as shown in Scheme III-14, Equations 1-2, we
63; (2) enolate form which is ready participated in some typical reactions (i.e reaction of an enolate with an oxaziridine) Therefore, we decided to make transformations based on compound
70 The expected synthetic pathways is demonstrated in Scheme III-14, Equation 3
Scheme III- 14 Expected synthetic pathway
In this approach, we planned to introduce a hydroxyl group into 70 via two synthetic paths
To achieve compounds 70A or 70B, oxidative cleavage of the alkene functional group was performed, resulting in compounds 72A, 72B, or 72C Subsequently, hydrolysis was conducted to yield the target compound (A-2) This process involves the introduction of a hydroxyl group into 70 through oxidation reactions (path a).
Compound 70 probably works as a phenol form as illustrated in Scheme III-14, Equation 1 Hence, we planned to introduce a hydroxyl group into 70 via oxidation reactions 29 As shown in Table III-6, a variety of oxidative reagents and influenced factors were screened Although the results indicated that the oxidation reactions could proceed and the C3 unit might be removed
By 1 H NMR analysis, unexpected elimination and racemized compounds were realized; however, these structures were not clearly determined
Table III- 6 Examination of various oxidants for the introduction of the hydroxyl group b) Introduction of the hydroxyl group via a reaction with an oxaziridine (path a)
Compound 70 probably works as a phenol form as illustrated in Scheme III-14, Equation 2 It was thus subjected to a reaction with an oxaziridine 30 was probably formed However, the reaction gave a complex mixture
Scheme III- 15 Examination for the introduction of the hydroxyl group into 70 by a reaction with an oxaziridine c) Introduction of the hydroxyl group via the reduction of the amide carbonyl (path b)
Scheme III- 16 Examination for the introduction of the hydroxyl group via the reduction of the amide carbonyl in 70
The presence of the hydroxyl group in compound 70 may facilitate the reduction of the amide carbonyl to hemiaminal by forming a chelation complex with a metal ion This interaction enhances the reduction process of the amide carbonyl.
As shown in Scheme III-16, the reduction was examined by the use of DIBAL-H However, desired compound 70B was not observed instead of the formation of undetermined compounds 70B-1 and 70B-2
3.3.3 Transformation via the reduction of the amide carbonyl in 61
The failure of previous reactions prompted a shift in focus to Scheme III-17, which outlines a novel approach for the removal of the C3 unit through a direct transformation of compound 61 This synthesis involves several key steps: first, the reduction of the amide carbonyl in 61 to produce 61A; second, the reduction of the hemiaminal group in 61A using a hydrazine agent to yield 61B; third, the oxidative hydrolysis of the thioacetal in 61 with hypervalent iodine to form 61C; and finally, the hydrolysis of 61C to achieve the target compound A-2.
Scheme III- 17 Expected synthetic pathway
The synthesis process commenced with the reduction of the amide carbonyl group in compound 61 Table III-17 summarizes the findings from these examinations, revealing that despite screening multiple reducing agents, the anticipated compound 61A was not detected.
Table III- 7 Examination of various reductants for the reduction of the amide carbonyl
3.3.4 Conclusion for the synthetic route 3
In this synthetic route, many transformations were executed but such the examined reactions were again not successful
The analysis of Synthetic route 2 and route 3 revealed that the low reactivity in the reactions can be attributed to two main factors: firstly, the aromaticity of the compounds due to the presence of a double bond; and secondly, the significant resonance stabilization occurring between the nitrogen-carbon and carbon-oxygen bonds in the resulting cycloadduct.
Removal strategy of the C3 unit via a reduction of N-N bond incorporated in the ring
of the produced cycloadduct (Synthetic route 4)
In light of the unexpected results from Synthetic routes 1-3, our study indicates that the characteristics of the produced cycloadduct must be modified Therefore, we propose the development of a new synthetic approach, referred to as Synthetic route 4, to address these challenges effectively.
Scheme III- 18 Expected synthetic pathway
The cycloadduct 56 was designed for modification through the reductive cleavage of the N-N bond within its ring, yielding compound 74 Subsequent transformations were conducted based on compound 74 to ultimately produce the target compound illustrated in B-1.
3.4.1 Examination for the reductive cleavage reactions of the N-N bond
To make a good use of an available functional group on the cycloadduct derivatives 69 and 61, the reduction of the N-N bond incorporated in their rings was preliminarily surveyed
Scheme III- 19 Examination for the reductive cleavage of N-N bond in 69
In Scheme III-19, the reduction of compound 69 using sodium in liquid ammonia resulted in a complex mixture, failing to yield the desired compound 69B This unsuccessful reaction may be attributed to the presence of a double bond in compound 69, which hindered the reduction process within the radical catalytic cycle.
As shown in Scheme III-20, 61 was next examined in the N-N bond reduction In this case, the expected reduction compound 75 was also not obtained while 56 was generated in 90%
Scheme III- 20 Examination for the reductive cleavage of N-N bond in 61
Recent primary examinations of the N-N bond reduction in compounds 61 and 69 indicate that the presence of an electrophilic moiety in their structures could negatively impact the N-N reduction process within the radical catalytic cycle.
To mitigate potential side effects, compound 56 was identified as an appropriate candidate for reduction The N-N bond in 56 was successfully reduced, resulting in the formation of product 74 with a satisfactory chemical yield of 58%, as illustrated in Scheme III-21.
Scheme III- 21 Examination for the reductive cleavage of N-N bond in 56
3.4.2 Introduction of a double bond into 74 and functional group transformations
With 74 in hand, we planned to introduce a double bond into its skeleton as a useful functional group for further transformations
The synthetic process of the introduction of a double bond into 74 includes 3 steps: (1) sulfenylation, (2) oxidation and (3) elimination, as described in Section 3.2.1
3.4.2.1 Introduction of a double bond in 74 via sulfenylation and selenation reactions a) Introduction of a double bond in 74 via sulfenylation using dimethyl disulfide
Scheme III- 22 Introduction of a double bond in 74 via sulfenylation using dimethyl disulfide
As shown in Scheme III-22, the introduction of a double bond into 74 via a sulfenylation using dimethyl disulfide was first examined
In this synthetic process, the electrophilic reaction of MeSSMe with the enolate of compound 74 yielded 76A with a recovery of 44% and 31% The oxidation of the methylsulfane substituent in 76A resulted in the formation of compound 77 with a yield of 50% and a recovery of 40% Subsequent elimination using pyridine in toluene reflux produced the desired compound 78 in trace amounts, alongside the regeneration of compound 74 The introduction of a double bond in compound 74 was further explored through selenation with phenylselenenyl chloride.
Scheme III- 23 Introduction of a double bond in 74 via selenation using phenylselenyl chloride
In Scheme III-23, compound 74 underwent selenation, leading to the unexpected formation of 76B at a yield of 27%, while 60% of the starting material was recovered Subsequently, the reduction of the phenyl selenane substituent in 76B was performed using NiCl2 and NaBH4.
3.4.2.2 Functional group transformations based on the introduced double bond a) Hydrolysis reactions
Although 76B and 78 were obtained in small amount due to the low chemical yield, we tried to make modifications relying on newly formed functional groups in their scaffold
As shown in Scheme III-24, 76B and 78 were subjected to the hydrolysis reaction The results indicated that a target compound as shown in B-2 was not produced although starting material was consumed
Scheme III- 24 Examination for hydrolysis reactions of 76B and 78
Our observations suggest that the target compound B-2 could be produced during the reaction; however, its high polarity in water may lead to its loss during purification in an aqueous medium Additionally, we are investigating the oxidative cleavage reaction involved in this process.
Scheme III- 25 Examination for an oxidative cleavage reaction of 78
In Scheme III-25, we anticipated that compound 78 would undergo oxidative cleavage of its double bond using NaIO4, followed by hydrolysis with NaOH to yield intermediate compound B-2 Subsequently, we aimed to protect the resulting amine moieties in B-2 to form the target compound B-3 However, the reaction resulted in an undetermined mixture, as indicated by the 1H NMR analysis of the crude products.
3.4.3 Introduction of the double bond after Boc-protection of amide and amine moieties
Based on above given results, we studied that the failure of the transformations based on the
74, 76B and 78 probably due to an existence of a proton on the amide and amine moieties
Therefore, we decided to protect these free protons to avoid such failures
3.4.3.1 Boc-Protection of amide and amine moieties
Scheme III- 26 Examination for Boc-protection of the amide and amine moieties
As shown in Scheme III-26, Boc-protection of amide and amine moieties 34 in 74 was performed and 79 was produced in 77% yield under examined conditions
3.4.3.2 Introduction of a double bond into 79 via a sulfenylation
With 79 in hand, we planned to introduce a double bond into its framework for further transformations The synthetic cycle of the introduction of a double bond into 79 includes 3 steps as mentioned, those are of the sulfenylation, oxidation and elimination
As shown in Scheme III-27, the synthesis began with a sulfenylation by using MeSSMe as an electrophile and LDA or KHMDS as a deprotonation reagent
However, desired compound 79A was not produced while stating material was recovered and other unidentified byproducts were realized
Scheme III- 27 Examination for an introduction of a double bond into 79
3.4.4 Introduction of a double bond after Bz- protection of amide and amine moieties 3.4.4.1 Bz-Protection of amide and amine moieties
We decided to change protective group from Boc-protection to Bz-protection because the introduction of the double bond in Boc-protected 79 has been failed
Table III- 8 Results of the Bz-protection of amide and amine moieties
Table III-8 illustrates the protection of amide and amine groups in compound 74 using benzoyl chloride The benzoyl-protected compounds 80 and 81 were synthesized with moderate to high chemical yields under the tested conditions (Entries 1-3).
3.4.4.2 Introduction of a double bond into 80 and 81 via a selenylation
With 80 and 81 in hand, the introduction of a double into their skeleton was investigated a) Introduction of a double bond into 80
Scheme III- 28 Examination of an introduction of a double bond into 80
As shown in Scheme III-28, an examination of an introduction of a double bond into 80 began with a selenation reaction by using PhSeCl in the presence of LDA However, desired compound
80A was not observed while stating material was almost recovered That meant the introduction of a double bond into 80 was not able to be continued b) Introduction of a double bond into 81
The introduction of a double bond into compound 81 was investigated through a selenation reaction, with the findings detailed in Table III-9, Entries 1-4.
The results indicated that desired compound 81B was produced in poor chemical yield (about
The investigation revealed a chemical yield of only 10%, indicating that while some material was recovered, the formation of unknown byproducts occurred under various conditions Due to the low yield of the selenation reaction, further transformations aimed at introducing a double bond were not pursued.
Table III- 9 Examination for an introduction of a double bond into 81
3.4.5 Functional group transformation via an introduction of a hydroxyl group into 74
The failure transformations based on compounds 76B, 74, 78, 79, 80 and 81 led us to investigate other synthetic approaches, that is of an introduction of a hydroxyl group into 74
3.4.5.1 Introduction of a hydroxyl group into 74 by reactions with an oxazaridine
The initial investigation into introducing a hydroxyl group into compound 74 through a reaction with an oxaziridine to produce compound 74A did not follow the anticipated synthetic pathway, as illustrated in Scheme III-29.
Scheme III- 29 Examination for an introduction of a hydroxyl group into 74 by reactions with an oxazaridine
3.4.5.2 Introduction of a hydroxyl group by a reduction of an amide carbonyl in 74
Scheme III- 30 Examination for a reduction of an amide carbonyl in 74
On an another try, the introduction a hydoxyl group into 74 via a reduction of the amide carbonyl in its framework was investigated Unfortunately, the similar situation was realized and
74B was not produced, as shown in Scheme III-30
3.4.6 Conclusion for the synthetic route 4
The synthetic method allowed for the smooth reductive cleavage of the N-N bond, leading to a series of transformations; however, the anticipated outcomes were not achieved in the reactions studied.
Summary for chapter III
Scheme III-31 shows a whole picture for the removal strategies of the C3 unit which have been performed
Scheme III- 31 General illustration for the removal strategies of the C3 unit
Despite the diverse synthetic approaches and extensive experiments conducted, the expected results from Synthetic routes 1-4 have not been achieved However, the insights gained from these studies prompted us to explore a more promising method, outlined as Synthetic route 5 in Chapter IV.