Metal- and Organo-Catalyzed Stereoselective Transformation of γ/δ-Hydroxyenones

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The content of the present thesis entitled "Metal- and Organo-Catalyzed Stereoselective Transformation of γ/δ-Hydroxyenones" is divided into five chapters based on the results achieved from the experimental works carried out during the entire course of the PhD research program is. The synthetic utility of this method was also illustrated by performing different reactions using tetrahydropyran derivatives.

Introduction

Over the past decades, the synthesis of γ/δ-hydroxyenones has been extensively developed as they are useful for the construction of various O-heterocycles. Indeed, several methods for the synthesis of hydroxyenones5 and their applications have been reported in the past decades.

Reactive sites of hydroxyenones

Hydroxyenones are versatile intermediates or building blocks6 in asymmetric synthesis for the preparation of various synthetically useful bioactive compounds such as tetrahydrofuran,7 1,3-oxazolidine,8 and 2-oxazolidinone9, etc.

Reported reactions with hydroxyenones

Several methods for the synthesis of complex molecules using hydroxyenones have been reported and some examples are listed below. In late 2001, Watanabe and co-workers14a developed the asymmetric oxy-Michael reaction between chiral ketone (derived from D-glucose and D-fructose) and γ/δ-hydroxyenones in the presence of catalytic amount of base.

Hydroquinine based oxy-Michael reaction

Asymmetric synthesis of 1,3-dioxolanes

Asymmetric synthesis of 1,3-oxazolidine

In 2012, Matsubara and colleagues also used γ-hydroxy α,β-unsaturated thioester as a model substrate instead of γ-hydroxy α,β-unsaturated ketone to achieve the oxy-Michael addition reaction with aldehydes using a quinidine-based thiourea catalyst. II with good enantiomeric excess and moderate diastereoselectivities (Scheme 1.4).19 The reaction proceeded via a hemiacetal intermediate for easy access of chiral acetal compounds. In the same year, the Hong research group illustrated a simple method for the synthesis of highly enantioselective cyclopentane carbaldehydes with four contiguous stereogenic centers.

Asymmetric synthesis of cyclopentanecarbaldehydes

They have reported the Michael–Henry reaction between 4-hydroxybut-2-enal and nitroalkenes in the presence of proline-derived catalyst IV via dienamine catalysis. Matsubara et al.21 also observed that isocyanate can be used as an efficient reactant for the cycloaddition reaction.

Asymmetric synthesis of 2-oxazolidinone

The stereochemistry of the product was strongly dependent on the addition order of the starting materials and the catalyst.

Asymmetric oxy-Michael reaction

Stereoselective 1,3-dioxanes are important structural frameworks and are converted into optically active 1,3-polyol motifs found in a number of polyketides, such as amphotericin B and atorvastatin. Thus, the group described a chiral phosphoric acid-catalyzed reaction between δ-hydroxyenones and aldehydes via hemiketalization followed by intramolecular oxy-Michael addition reaction to obtain the enantioselective 1,3-dioxanes with a single diastereomer (Scheme 1.8).5i.

Chiral phosphoric acid catalyzed asymmetric oxy-Michael reaction

Asymmetric synthesis of diaxazinane and dioxazepane heterocycles

Chloramphenicol based urea catalyzed oxy-Michael reaction

Asymmetric synthesis of acetal via dimerization

Cyclization reaction

In this context, a number of methods have been developed for the construction of heterocyclic compounds through intramolecular cyclization reactions. For example, Taylor group29 reported an efficient base-mediated intramolecular oxy-Michael reaction of γ-hydroxyenones containing attached hydroxyl moiety for the synthesis of tetrahydropyran derivatives (Scheme 1.13).

Synthesis of tetrahydropyran

Intramolecular cyclization via hetero-Michael27,28 reaction is an important alternative convenient and atom-economical method that has been used for the synthesis of various heterocyclic moieties that are important building blocks in organic synthesis and materials science.

Asymmetric synthesis of tetrahydrofuran

Organocatalytic intramolecular oxy-Michael reaction

Asymmetric synthesis of β-mercaptolactones C. Michael reaction

Asymmetric alkenylation via Michael reaction

Cyclopropane ring formation

Cyclopropane ring is one of the simplest structural structures in organic chemistry and became a versatile synthetic intermediate for the synthesis of various natural products.34 The higher ring strain of the cyclopropane ring made it easier to cleave the carbon-carbon bond compared to other cyclic compounds. . A variety of methods have been reported for the synthesis of cyclopropane rings.35 This compound was also formed from γ-hydroxyenones (in situ derived from 1,2 dioxins) as developed by the Taylor group under mild reaction conditions using ester-stabilized ylide via a five member of O−P intermediate link (scheme 1.18).36.

Cyclopropane ring formation

For selected books on heterocyclic chemistry see: (a) Modern Heterocyclic Chemistry; Alvarez-Builla, J., Vaquero, J. b) Advances in Heterocyclic Chemistry; Gribble, G.

Introduction

General strategy to access carbonyl compounds from allylic alcohols 2.2 General mechanism for transition metal catalyzed isomerization reaction

Deprotonation of the allylic alcohol resulted in the initial formation of the transition metal alkoxide complex. Further, the intramolecular conjugate addition of hydride to the enal led to the formation of an oxa-allyl metal species, which after protonation released the metal catalyst and the free enol and finally formed the corresponding carbonyl compound by tautomerization of the enol.

Scheme 2.2: General mechanism for transition metal catalyzed isomerization of allylic alcohol

Transition metal catalyzed redox isomerization reactions
Iron-catalyzed: 10
Ruthenium-catalyzed: 11,12
Rhodium-catalyzed: 13,14
Iridium-catalyzed 15,16

In recent decades, many transition metal complexes have been widely used for the redox isomerization reaction9 of readily available allylic alcohols to saturated carbonyl compounds, which are very valuable raw materials in organic chemistry. Vast synthetic methodologies involving the transition metal-catalyzed redox isomerization reaction of allylic alcohols have been reported in the literature.

Organocatalytic redox isomerization reactions

Importantly, organocatalytic redox isomerization18,19 of allylic alcohols has been identified as an attractive alternative strategy compared to metal-catalyzed redox isomerization. Several acid- and base-catalyzed redox isomerizations of γ-hydroxyenones to 1,4-diketones have been previously reported. 20 Unfortunately, these previously described methods suffered from limitations related to narrow substrate scope, lower yields, and high reaction temperature.

DABCO catalyzed redox isomerization

In 2010, Miles and colleagues revealed DABCO-catalyzed isomerization of 6-hydroxy-2H-pyranones to 1,2,5-triketones in moderate to good yields (Scheme 2.5).22

Phenanthroline-tert-butoxide catalyzed redox isomerization

In 2016, a mild base (TBD) catalyzed approach to the isomerization of electron-deficient allylic alcohols and ethers has been developed by Matute and co-workers (Scheme 2.7).24.

TBD catalyzed redox isomerization of allylic alcohols

DABCO catalyzed redox isomerization of propargylic alcohols

Synthetic methodologies for 1,4-dicarbonyl compounds

Stetter reaction for the synthesis 1,4-dicarbonyl compounds

Synthesis of 1,4-dicarbonyl compounds

Cobalt catalyzed synthesis of 1,4-dicarbonyl compounds

Result and discussion

To improve the yield of the product, different solvents were screened under similar reaction conditions. Poor yields 45% and 52% of the isomerized product 3-benzoylpropanal (2a) were obtained with Et3N and DIPEA, respectively (Table 2, entries 3-4).

Table 2. Catalyst and Temperature Screening

Substrate scope

Interestingly, ortho substitution on the aryl group did not change the outcome of the reaction, and a good yield of 82% was achieved with 2-methyl-substituted arylenone 1l. 1-Naphthyl-substituted enone 1m was also involved in the reaction, and a good yield of 75% was obtained for the desired product 2m.

Plausible reaction mechanism

Proposed mechanistic pathway

Experimental section General information

Otherwise, the residual proton resonance and carbon resonance of the solvent (CHCl3, δ(1H) 7.26 ppm, δ(13C) 77.23 ppm were used for calibration. IR spectra were recorded on an FT-IR instrument at normal temperature by Make KBr pellets and sample with KBr (IR quality).

General procedure for the synthesis of α-unbranched trans-γ- hydroxyenones 1a-1s

General procedure for the synthesis of products 2a-2y

References
Characterization data of products 4-Oxo-4-phenylbutanal (2a)
Selected NMR spectra of products
Introduction
Known methods towards the synthesis of substituted tetrahydropyrans

Although a large number of reactions based on the stereocontrolled and racemic approach have been developed for the construction of tetrahydropyrans, there is still a space to synthesize tetrahydropyran ring with different substitutions. In recent decades, tetrahydropyrans have been used as an effective building block in organic synthesis, thus a large number of synthetic strategies have been developed for the preparation of tetrahydropyran rings.9 Some of the representative examples have been shown in this section.

Figure 3.1: Biologically active natural products containing tetrahydropyran units

Synthesis of tetrahydropyran using copper(II) triflate

Synthesis of tetrahydropyran via [4 + 2] cycloaddition reaction

Intramolecular oxy-Michael cyclization reaction

Iron(III)-catalyzed cyclization reaction for the synthesis of tetrahydropyran Recently, iminophosphoric acid catalyzed asymmetric synthesis of tetrahydropyran via

Asymmetric synthesis of tetrahydropyrans

In the last few years, due to their unique reactivity profile, donor-acceptor cyclopropanes (DA cyclopropanes) have served as important synthetic intermediates in organic chemistry for the preparation of highly substituted carbo- and heterocycles via a dipolar cycloaddition reaction, thus targeting the development of a wide range of anylation reactions.15 Among by [3 + n]-annulation reactions, the [3 + 3]-annulation reaction allows rapid access to valuable six-membered rings.16,17 For this purpose, a stable 1, A 3-zwitterion or a substrate capable of producing a dipolar species was needed, to be able to react with the reactive 1,3-dipole in situ generated from DA cyclopropane in the presence of Lewis acid or basic catalysts. For example, Kerr and co-workers revealed Lewis acid-catalyzed nucleophilic ring opening of a cyclopropane 1,1-diester with propargyl alcohol and subsequent konia-ene cyclization to afford substituted tetrahydropyrans in high yields and nearly 1:1 diastereomeric ratio (Scheme 3.6). 18.

Synthesis of tetrahydropyrans using DA cyclopropane

Synthesis of triazinines using DA cyclopropane

The Zhang group exploited the [3 + 3] annulation reaction of cyclopropane 1,1-diester with in situ generated mercaptobenzaldehyde catalyzed by scandium(III) triflate to access polysubstituted tetrahydrothiopyranols with moderate diastereoselectivity (Scheme 3.8).20.

Synthesis of tetrahydrothiopyranols using DA cyclopropane

Synthesis of tetrahydro-1,2-oxazines using DA cyclopropane

Synthesis of tetrahydropyridazines using DA cyclopropane

Result and discussion

Literature reports revealed that allylic alcohols have never been used in a donor-acceptor (DA) cyclopropane reaction so far, so we envisioned that γ-hydroxyenones could be suitable 1,3-conjugating reagents for tandem nucleophilic addition—Michael reaction. Encouragingly, the yield was increased to 85% with Sc(OTf)3 and the same diastereomeric ratio of 2:1 was observed (Table 1, entry 10).

Substrate scope

Although the result was better with o-anisyl substituted diester 2f, which gave the products 3p/3p′ in a yield of 68% and a ratio of 1:1.3. 1,1′-Bi-2-naphthol (BINOL) and tert-leucine-derived BOX catalyst L1 afforded the products 3a/3a′ with very poor enantioselectivities (<5% ee).

Asymmetric version of the reaction

Synthetic transformations of the products

Experimental section General information

Chemical shifts were reported in parts per million (ppm) and the remaining solvent peak was used as an internal reference: proton (chloroform δ 7.26), carbon (chloroform δ 77.23). IR spectra were recorded using an FT-IR Instrument at room temperature by making KBr pellets and grinding the sample with KBr (IR grade).

General procedure for the synthesis of annulation products 3a/3a′-3r/3r′

Representative procedure for asymmetric synthesis

General procedure for the synthesis of compounds 4/4′

General procedure for the synthesis of compounds 5/5′ and 6

References
Characterization Data of Products
Selected spectra of products
Introduction
Synthesis of substituted furan derivatives

In recent decades, several approaches have been developed for the synthesis of substituted furans.6 In general, Feist-Bénary condensation and Paal-Knorr condensation are one of the traditional and established methods to construct the substituted furans. A new strategy for the synthesis of substituted furan-allene derivatives was demonstrated by Wang and colleagues.

Table 1. Crystal data and structure refinement for compound 6

CuI catalyzed synthesis of substituted furan allenes

This group has reported the coupling reaction between ene-ketone and terminal alkyne using Cu(I) catalyst (Scheme 4.2).8. The Antonchick group developed an efficient method to construct multisubstituted furans from readily available starting materials acetophenones and activated alkynes under Cu(I) salt catalysis; and di-tert-butyl peroxide was used as an external oxidant.

Synthesis of multisubstituted furans

Synthesis of 2,5-disubstituted furans 4.3 Reaction with donor-acceptor oxiranes

Proposed routes for the oxirane bond cleavage reactions (mode A: C−O bond cleavage and mode B: C−C bond cleavage). For example, Zhang group reported highly diastereoselective Lewis acid-catalyzed reaction of 1,3-dipolar oxiranes and aldehydes for the synthesis of cis-2,5-di-substituted 1,3-dioxolanes at ambient temperature in excellent yields (Scheme 4.5). 12.

Synthesis of substituted 1,3-dioxolanes

Synthesis of substituted dihydrofurans

Synthesis of 2,4-oxazolidine derivatives

Synthesis of 3-oxazoline derivatives

Result and discussion

A strong Brønsted acid such as triflic acid also gave the furan product 3a in moderate yield (Table 1, entry 3). The reaction was also carried out at higher temperature in DCE solvent, but lower yields were observed.

Substrate scope

Here, a variety of substitutions on the aryl ring were also compatible for the reaction. However, the phenyl group containing oxiranediaster 2b provided moderate yield (37%) of product 3p. Finally, a 1-naphthyl group containing oxirane 2p was incorporated into the reaction and a good yield of 65% was achieved for product 3z′′.

Proposed mechanism for the formation of furan

Hammett analysis

Finally, log(KX/KH) versus σp. substituent constant) is plotted (Figure 4.5) and the value of the rate constant is determined, as shown in Table 3. The data for σp are also provided. substituent constant) of various p-substituted oxiranes from the literature. From this graph (Figure 4.5), the negative value of the reaction constant (slope = −1.39) was observed, indicating that the greater the electron dispersion of the benzylic carbon of oxiranes, the slower the reaction rate.

Figure 4.4: Time vs %Conversion for p-OMe-substituted oxiranes using different equivalent (left) and ln(Initial Rate) vs ln[p-OMe oxirane], to determine the rate of the reaction (right)

Synthetic transformations of 3a and 3g

Experimental section General Information

For the experiments, all starting materials and reagents were purchased from standard commercial sources or prepared in the laboratory. General procedure for the synthesis of trans-γ-hydroxyenones 1a-1o Trans-γ-hydroxyenones were prepared according to the reported procedure.19 Trans-γ-hydroxyenones were prepared according to the reported procedure.19.

General Procedure for the Synthesis of DA-oxiranes 2a-2p

General procedure for the synthesis of compounds 5 and 6

General procedure for the synthesis of compounds 7 and 8

References
Selected NMR spectra of products
Introduction
Known strategies for Michael and acyl transfer reactions

Previously, few groups independently disclosed the organocatalytic asymmetric conjugate addition of α-nitroketones8 to β,γ-unsaturated α-keto esters, followed by acyl transfer reaction to the keto group. Interestingly, other electron-deficient carbonyl compounds as well as nitroolefins have been found to be unreactive.9.

Table 1. Crystal data and structure refinement for compound 3a

Scheme 5.1: Indane derived thiourea catalyzed asymmetric Michael/acyl transfer reaction

Scheme 5.2: Pyrrolidine based thiourea catalyzed asymmetric Michael/acyl transfer reaction

Later, the Kwong group developed a cinchona-derived, thiourea III-catalyzed reaction of β,γ-unsaturated ketoesters with α-nitroketones in ether solvent to yield the corresponding products with moderate to good enantioselectivities (Scheme 5.3).11.

Scheme 5.3: Cinchona derived thiourea catalyzed asymmetric Michael/acyl transfer reaction

Organocatalytic asymmetric Michael/Hemiketalization/Retro-aldol reaction

Result and discussion

Finally, the best catalyst proved to be quinine-derived squaramide catalyst XIII, which provided product 3a in 93% yield and 96% ee (Table 1 , entry, entry 10). When the reaction was carried out at 0 oC in toluene, the enantioselectivity remained the same, but the yield decreased significantly (Table 2, entry 7).

Substrate scope

In addition, the heteroaromatic enone 1l was tested in the reaction and high enantioselectivity for product 3l was observed. Finally, the aliphatic nitroketone 2q was engaged in the reaction and gave the product 5o in good yield and high enantiomeric excess.

Synthetic transformation of 3a

1-Naphthyl-containing nitroketone also underwent the reaction with 4a, leading to the formation of the product 5m with excellent enantioselectivity (96%). Interestingly, the reaction between nitromethane (9) and la was very slow, although the enantioselectivity for the corresponding product 8 was high (Scheme 5.10).

Control experiments

An experiment was also performed using TBS-protected enone (10) and α-nitroketone (2a) in the presence of catalyst VII and the single Michael addition product was formed in 73% yield with 1:0.8 diastereomeric ratio with 96% ee for the major diastereomer. From these experiments, it can be concluded that Michael addition step (1st step) is the stereo control step in our reaction.

Plausible mechanism for the formation of 3a

Experimental section General Information
General procedure for Michael/Acyl transfer products 3a-3z'''' and 5a-5o
General procedure for the synthesis of compounds 7
General procedure for the synthesis of compounds 8 This compound was prepared according to literature procedure. 20

References

General procedure for the synthesis of trans-δ-hydroxyenones 4a-4e Trans-δ-hydroxyenones were prepared according to literature procedure.17. Then the residue was purified by flash column chromatography with 10% ethyl acetate/hexane to obtain the desired product 7.