Organocatalytic reactions of 3 hydroxy 2 pyrone and n arylsulfonyl 3 hydroxy 2 pyridone 2

Under high temperature conditions, DA reactions can proceed smoothly followed by decarboxylation reaction to remove CO2.. Tsuboi’s group also used 1 to react with 1,4-naphthoquinone in r

Chapter 2

Reactions of 3-hydroxy-2-pyrone

2.1 3-Hydroxy-2-pyrone

3-Hydroxy-2-pyrone 1 is a compound that can be synthesized from the pyrolysis

of mucic acid in the presence of potassium dihydrogen phosphate and phosphorous pentoxide (Scheme 2.1).1 A mixture of products is obtained and by tuning the pH of the mixture carefully, extraction can be done to singly extract the pyrone as a clean product that is suitable for carrying out reactions Ether is used as a solvent to extract the product into the organic phase using a continuous extraction process

Scheme 2.1 Synthesis of 1 from mucic acid

Corey et al had used 1 as a vinylketene equivalent that reacted like a diene in the

Diels-Alder process (Figure 2.1).2

Figure 2.1 3-Hydroxy-2-pyrone 1 and vinylketene

Under high temperature conditions, DA reactions can proceed smoothly followed

by decarboxylation reaction to remove CO2 In this way, the synthesis of a variety of

dihydrophenolic compounds was realized In the report, thermal conditions were required for the reactions to take place The dihydrophenolic products obtained contained one chiral centre (Scheme 2.2) The asymmetric version was not evaluated in the communication

CO2Me

OH

CO2Me Me

Scheme 2.3 Reaction of 1 and 1,4-naphthoquinone

Tsuboi’s group also used 1 to react with 1,4-naphthoquinone in refluxing PhMe in

the presence of NEt3 (Scheme 2.3).3 A Diels-Alder reaction is likely to be the first step followed by the decarboxylation reaction under high temperature conditions This is

similar to the previous route reported by Corey (Scheme 2.2) except that a base (NEt3) is used to facilitate the DA reaction This reaction provided access to anthraquinone derivatives

Scheme 2.4 Reaction of 1 with chiral acrylates and its synthesis leading to (-)-eutipoxide

The base-catalyzed DA reaction of 1 was also extended to the use of a chiral

acrylate as a dienophile (Scheme 2.4).4 The chiral 2-oxazolidinone moiety was responsible for inducing the asymmetry in the bicycloadduct The product was obtained

in >70% yield The chiral auxiliary could be transformed to a methyl ester group by MeONa/MeOH Subsequently, several steps were carried out successfully to yield the final product By switching the chiral centre on the 2-oxazolidinone group, the synthesis

of (+)-eutipoxide could also be achieved

2.2 2-Pyrones and derivatives

The majority of 2-pyrone reactions lies in its use as a diene in DA reactions 1

was mentioned in the earlier part (Section 2.1) and that a small amount of base is usually sufficient to catalyze its DA reaction with other dienophiles This is an added advantage

as this provides a pathway whereby milder conditions can be used for the DA reactions However, a large part of 2-pyrone chemistry also involves compounds that contain no hydroxyl group at the 3-position To-date, much of the DA reactions of 2-pyrones (no hydroxyl group at 3-position) require either high temperature or pressure for them to work There are no reports that demonstrate that a base is capable of catalyzing DA reactions of such 2-pyrones On the other hand, the products they produce are significantly useful in the course of synthetic organic chemistry It is thus worthwhile to study these reactions and understand their mechanisms and to develop milder methods to carry them out

Scheme 2.5 Reaction of 2-pyrone with vinyl acrylate in a consecutive Diels-Alder

reaction

MarkÓ et al performed a consecutive DA reaction using just the 2-pyrone and a

vinyl acrylate in a one-pot procedure (Scheme 2.5).5 The conditions for the first DA required a high pressure of 19kbar delivering a good yield of 95% The high pressure will

not affect the overall molecular structure Subsequently, refluxing the product at a high temperature of 200oC promotes the decarboxylation reaction removing a molecule of CO2giving a dihydrobenzene core With the presence of a diene and an olefin in the same molecule, an intramolecular DA reaction took place to yield the tricyclic compound as shown

The hydroxyl group of 1 was protected with a Me group and used as a diene.1 In this case, a base might not be able to catalyze a DA reaction as there is no hydroxyl group

It was reacted with acetylene dicarboxylate under reflux conditions (Scheme 2.6) Decarboxylation took place thereafter and an aromatic ring was formed Like the example shown earlier (Scheme 2.3), this is also a route to attain phenols and its derivatives

Scheme 2.6 Reaction of 3-methoxy-2-pyrone and acetylene type dienophiles under reflux

reactions (with ether type olefins) to give DA products as well The unique ambiphilic characteristic is not commonly found in a single diene but it is well embodied in this 2-pyrone molecule On the other hand, 5-bromo-2-pyrone was found to give cycloadducts slowly under thermal conditions with both electron-poor and electron-rich

Scheme 2.7 Reaction of 3-bromo-2-pyrone and various dienophiles

O O

Br

R

o C, 2-5d 83-100%

O

O

R Br

R = CN, COMe, CO 2 H, OSiMePh 2, p-Br-C6 H 4

Scheme 2.8 Reaction of 5-bromo-2-pyrone and various dienophiles

dienophiles Despite the slow reaction rate, the bromo group at the 5-position has increased the diene reactivity as a high reaction temperature is no longer required (Scheme 2.8) Milder conditions can equally be applied for a reaction to take place

Posner also reported commercially available silica gel as another inexpensive promoter for the DA reaction of the optically active pyrone lactate ester and benzyl vinyl ether (Scheme 2.9).9 The diastereoselectivity was 58% and the yield was 60% when it was carried out in toluene at -30oC

O O

O

Me

O Bn +

SiO 2 , -30oC PhMe 60% yield d.e 58%

O

OBn H

Scheme 2.9 Reaction of optically active pyrone lactate ester with benzyl vinyl ether using

silica gel as a promoter

Scheme 2.10 Reaction of 3-carbomethoxy-2-pyrone with vinyl ethers in the presence of

lanthanide shift reagents

This is another example that showed 2-pyrones can take part in inverse electron demand DA reactions 3-Carbomethoxy-2-pyrone can react with vinyl ethers to give DA products in the presence of lanthanide shift reagents (Scheme 2.10).10 The authors reported that the use of strong Lewis acids can destroy the cycloadducts by gearing the products towards decarboxylation Strangely, Yb(OTf)3 alone does not act as the catalyst

but the addition of (R)-BINOL generates a new active catalyst that promotes the reactions with moderate to good enantiomeric excess

Corey also utilized a pyrone in the synthesis of the sesquiterpene (±)-occidentalol (Scheme 2.11).11 The initial step involved reacting the pyrone with 4-methyl-3-cyclohexenone at 150oC under nitrogen for 24h Decarboxylation occurred under the reflux conditions to yield the basic decalin structure which upon further reactions gave the racemic alcohol The yield of the DA product was about 25-40% Further transformations led to the racemic product (±)-occidentalol

O O MeO2C

O

Me

- not detected in reaction mixture

- decarboxylation occured under reflux conditions

CO2Me

O Me

Me Me

OH (±)-occidentalol

several steps

Scheme 2.11 Corey’s synthesis of (±)-occidentalol from 3-carbomethoxy-2-pyrone

Previous examples had made used of either 3- or 5- substituted 2-pyrones for reactions However, Cho and coworkers had shown that even 3,5-disubstituted 2-pyrone can be utilized for DA reaction (Scheme 2.12).12 The yield for the cycloadduct was acceptable and the product was used in the synthesis of (±)-joubertinamine

Scheme 2.12 Reaction of 3-aryl-5-bromo-2-pyrone with vinyl thioether

Although 1 has a structure that has a few functional groups (hydroxyl group,

diene group and ester group), the major study lies in its use as a dienophile in Diels-Alder reactions Its structural similarity to 4-hydroxy coumarin and its existence as a readily available enolate equivalent could have prompted its use as a donor in Michael or Aldol type reactions

OH another point

of attack

(gamma-attack)

Figure 2.2 Comparing various points of attack (as a Michael donor) in

3-hydroxy-2-pyrone and 4-hydroxycoumarin

There are 2 possible sites of attack in 3-hydroxy-2-pyrone which are namely the alpha site and the gamma site with respect to the alcohol (Figure 2.2) Deng reported that

1 can react with α,β-unsaturated ketones to give Michael products.13 The products were

observed to be an attack of 1 from its γ-position N-sulfonyl-3-hydoxy-2-pyridone was

also observed to do Michael reactions with β-nitro styrenes The details of this reaction will be described in the following chapter

JØrgensen used a simple chiral imidazolidine acid catalyst to catalyze the Michael reaction between 4-hydroxycoumarin and α,β-unsaturated enones (Scheme 2.13).14 Fairly good yields were obtained and the enantioselectivity of the product was more than 80% This route could successfully provide a route to the anti-coagulant Warfarin Recrystalliztion using acetone/water mixture could increase the enantiomeric excess of the Michael product to >95%

Scheme 2.13 Organocatalytic Michael reaction of 4-hydroxycoumarin and

α,β-unsaturated enone

2.3 Synthesis of 3-hydroxy-2-pyrone derivatives

The study on the reactions of 1 can be impeded by the difficulty in developing the

substrate variants The addition of different substituents on 3-hydroxy-2-pyrone remains

a difficult task for synthetic chemists A route developed by Tsuboi requires a linear multi-step synthesis to obtain the 4-halo-3-hydroxy-2-pyrone (Scheme 2.14).15 The substituent on the 6-position can be altered accordingly The attachment of a halogen on the 4-position facilitates coupling reactions to be done However, the fact that several steps are required for obtaining the 3-hydroxy-2-pyrones (6-substituted, 4-substituted, or both) may actually slow down the research on the chemistry of their reactions

Reagents and conditions: (i) t-BuOK (1.2 eq.), CHCl2CO2Et (1.0 eq.), THF (72% yield); (ii) K2CO3, H2O-acetone; (iii) NaBH4, THF-MeOH, 0oC; (iv) DMP, PTSA (cat.), acetone,

rt, (71% yield, three steps), (v) DIBAL-H (1.5 eq.), Et2O, -78oC; (vi) t-BuOK,

CHCl2CO2Me (1.0 eq.), THF, (71% yield, two steps)

Scheme 2.14 Synthesis leading to 4-halo-3-hydroxy-2-pyrone

2.4 Asymmetric reactions of 3-hydroxy-2-pyrone

Scheme 2.15 DA reaction of 1 and 2c

The reaction between 3-hydroxy-2-pyrone and N-benzyl maleimide can be

catalyzed by a small amount of base (Scheme 2.15) Preliminary studies included the screening of the following oxazoline-containing compounds as catalysts for the reactions (Figure 2.3) These bis-oxazolines (BOX) are commonly used for metal-catalyzed reactions and had their roles as ligands binding to the metal centre.16 To the best of our knowledge, there was only one report describing that these ligands could catalyze the DA reactions of anthrones and maleimides without the presence of any metal ions.17 The enantiomeric excess was moderate at about 70% but the yields were more than 90%

To our surprise, they can also catalyze the DA reaction of 1 and N-substituted

maleimides A 10 mol% loading of the catalyst is sufficient for the reaction to proceed to

completion They were used as catalysts for the reaction of 1 and 2c, but the best result was 40% enantiomeric excess which was obtained with A5

Figure 2.3 BOX ligands used as catalysts for the DA reactions of 1

Our group has a major interest in using bicyclic guanidines as catalysts for

enantioselective reactions, particularly the C2-symmetric tert-butyl catalyst (Scheme

2.16).18 Applying 10 mol% of the tert-butyl catalyst for the DA reaction of 1 and 2c, an

enantiomeric excess of 45% can be obtained for the cycloadduct

Scheme 2.16 DA reaction catalyzed by C2-symmetric bicyclic guanidine catalyst

Nakatani had demonstrated the use of cinchona alkaloids as catalysts in the DA

reaction between 1 and various dienophiles Deng perfected the reaction with various

dienophiles by fine tuning the structures of the alkaloids used With this in mind, we were certain that a bifunctional catalyst containing a tertiary amine and a hydrogen bond donor would be useful in the DA reactions of this class of dienes

Chiral pyrrolindinyl sulfonamides (CPS) 3a-d contain a pyrrolidine group

(hydrogen-bond acceptor) and a sulfonamide group (hydrogen-(hydrogen-bond donor) They can be easily synthesised from commercially available amino alcohols and they were shown to be effective promoters in the tandem conjugate elimination-addition reactions of allylic bromides and thiomalonates (Scheme 2.17).19 Encouraged by this finding we tested these CPS (Figure 2.4)

as catalysts in the DA reactions of 1 They were found to be great catalysts for the Alder reactions of 1 as well Excellent yields were obtained and good to moderate

Diels-enantiomeric excess (up to 88%) were achieved (Table 2.1)

Scheme 2.17 SN2’ reaction of cyclic allylic bromides and dithiomalonates promoted by

CPS 3a-d

Figure 2.4 Structures of chiral pyrrolidinyl sulphonamides (CPS) 3a-d

The DA reaction completed in most common solvents such as CH2Cl2 and THF Polar solvents such as methanol and acetonitrile were found to decrease the

Table 2.1 Screening of catalysts and solvents for the Diels Alder reaction of 1 and

enantioselectivity drastically (Table 2.1, entries 9 & 10) The best results were obtained when CH2Cl2 was used as the solvent Other N-substituted maleimides were synthesised

and they gave similar enantiomeric excess (Table 2.1, entries 14 & 15) The best result was

obtained when the benzyl catalyst 3a was used By lowering the temperature, the

enantiomeric excess could be improved as can be seen from entries 11-15 This particular

reaction is unique because the major isomer produced is the exo isomer compared to most other reports where endo product is the major isomer

N O

O

OH O +

O O

HO O

1

Scheme 2.18 DA reaction of 1 and terminal olefin catalyzed by 3b

To demonstrate that the system is not limited to cyclic dienophiles, a terminal

olefin was also used in the DA reaction with 1 (Scheme 2.18) A slower reaction rate was

observed but a steady conversion of the product was obtained The enantiomeric excess was about 70% However, the reaction rate was rather slow (72h) such that optimization

of the reaction condition by lowering the temperature was not carried out

Scheme 2.19 DA reaction of 1 and 2d

The amino indanol which was developed for the asymmetric DA reactions of

N-sulfonyl-3-hydroxy-2-pyridone (more about this reaction would be discussed in the next chapter), was also found to be a suitable catalyst for the Diels-Alder reaction of 3-

hydroxy-2-pyrone and N-mesityl maleimide (Scheme 2.19) The yield was about 95% with an endo:exo ratio of about 3:1 The major product had a higher enantioselectivity of

90% With this, it was demonstrated that several catalysts developed in our lab were able

to catalyze the reaction of 3-hydroxy-2-pyrone and various dienophiles giving moderate

to high enantioselectivities

The enantiomer of product 5a was also used in the synthesis of the key

intermediate of an SP antagonist RPR107880 (Figure 2.5).20 Substance P (SP) is a small peptide classified in the tachykinine family and it behaves like a neurotransmitter The protecting group used in this synthesis was benzyl instead of the mesityl (2,4,6-C6H2) group In this report, the authors used quinine as the catalyst and the best enantiomeric excess obtained for the cycloadduct was 63% The method they used for obtaining the optically pure product was by recrystallization of the cycloadduct